6-O-Carbamoyl ketolide antibacterials

ABSTRACT

6-O-Carbamoyl ketolide antibacterials of the formula:                    
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, X′, Y, and Y′ are as described herein and in which the substituents have the meaning indicated in the description. These compounds are useful as antibacterial agents.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit under 35 U.S.C. § 119(e) of prior application Ser. No. 60/251,547, filed Dec. 6, 2000.

FIELD OF THE INVENTION

The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.

BACKGROUND OF THE INVENTION

Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide-resistant Streptococcus pneumoniae. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.

The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:

EP 216,169 and U.S. Pat. No. 4,826,820 to Brain et al. disclose antibacterially active 6-carbamate erythromycin derivatives stated to “have antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.”

U.S. Pat. No. 5,444,051, U.S. Pat. No. 5,561,118, and U.S. Pat. No. 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formulae

wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.

U.S. Pat. No. 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.

WO 97/17356 (Or et al.) discloses tricyclic erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.

WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula

wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.

WO 99/21864 (Or et al.) discloses 6,11-bridged erythromycin derivatives having antibacterial activity.

SUMMARY OF THE INVENTION

The invention provides compounds of Formula 1:

wherein:

R¹ and R² are independently selected from hydrogen, optionally substituted C₁-C₈-alkyl, optionally substituted —CH₂C₂-C₈-alkenyl, and optionally substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R¹ and R² are not both hydrogen;

R³ is selected from hydrogen;

R⁴ is selected from hydrogen, halogen, and hydroxy;

R⁵ is hydrogen or a hydroxy protecting group;

R⁶ is selected from hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;

X and X′, together with the carbon atom to which they are attached, form C═O, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and

Y and Y′, together with the carbon atom to which they are attached, form C═O, —CHOH, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from hydrogen, alkyl, alkenyl and alkynyl;

or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.

Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.

The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula 1.

The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1.

Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.

DETAILED DESCRIPTION

Relative to the above description, certain definitions apply as follows.

Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

Unless specified otherwise, the terms “alkyl”, “alkenyl”, and “alkynyl,” whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. The term “alkyl” refers to straight or branched chain hydrocarbons. “Alkenyl” refers to a straight or branched chain hydrocarbon with at least one carbon-carbon double bond. “Alkynyl” refers to a straight or branched chain hydrocarbon with at least one carbon-carbon triple bound. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. “Alkoxy” radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. “Cycloalkyl” groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. The alkyl, alkenyl, alkynyl, cycloalkyl group and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —COOR_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl.

The term “acyl” as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term “Ac” as used herein, whether used alone or as part of a substituent group, means acetyl.

The term “halo” or “halogen” means fluoro, chloro, bromo and iodo. (Mono-, di-, tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.

“Aryl” or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.

Whether used alone or as part of a substituent group, “heteroaryl” refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, N-oxo-pyridyl, 1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, and thienothienyl. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.

The terms “heterocycle,” “heterocyclic,” and “heterocyclo” refer to an optionally substituted, fully saturated, partially saturated, or non-aromatic cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolinyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; 2-oxazepinyl; azepinyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; benzothiopyranyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; benzopyranyl; dihydrobenzopyranyl; indolinyl; chromonyl; coumarinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.

Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.

Designated numbers of carbon atoms (e.g., C₁₋₈) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

The term “hydroxy protecting group” refers to groups known in the art for such purpose. Commonly used hydroxy protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), which is incorporated herein by reference. Illustrative hydroxyl protecting groups include but are not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethythiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethyl silyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl; acyl and aroyl such as acetyl, pivaloylbenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acylaryl.

Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.

The phrase “a pharmaceutically acceptable salt” denotes one or more salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicyclic acid and the like. Suitable salts are furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)₂, Al(OH)₃, piperidine, morpholine, ethylamine, triethylamine and the like.

Included within the scope of the invention are the hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate, and sesquihydrate forms. The present invention also includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The term “subject” includes, without limitation, any animal or artificially modified animal. As a particular embodiment, the subject is a human.

The term “drug-resistant” or “drug-resistance” refers to the characteristics of a microbe to survive in presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.

The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.

In particular, compounds of Formula 1 wherein R¹ and R² are independently selected from hydrogen, substituted C₁-C₈-alkyl, substituted —CH₂C₂-C₈-alkenyl, and substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R¹ and R² are not both hydrogen;

R³ is selected from hydrogen;

R⁴ is selected from hydrogen, halogen, and hydroxy;

R⁵ is hydrogen or a hydroxy protecting group;

R⁶ is selected from hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thoalkyl group;

X and X′, together with the carbon atom to which they are attached, form C═O, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and

Y and Y′, together with the carbon atom to which they are attached, form C═O, —CHOH, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from hydrogen, alkyl, alkenyl and alkynyl; are embodiments of the present invention for such purposes. More particularly, R² is hydrogen, R⁴ is hydrogen or fluorine, X and X′ form C═O together with the carbon atom to which they are attached, and Y and Y′ form C═O together with the carbon atom to which they are attached.

Compounds of Formula 1, which are represented by Formula 1′

wherein R¹, R², R³, and R⁴ are as described above are also embodiments of this invention. More particularly, R² and R³ are hydrogen and R⁴ is fluorine.

Compounds of Formula 1, which are represented by Formula 1″

wherein R¹, R², R³, and R⁴ are as described above, are further embodiments of this invention. More particularly, R² and R³ are hydrogen and R⁴ is fluorine.

Compounds of Formula 1, wherein R⁵ may be selected from acyl and aroyl are further embodiments of this invention.

The following are yet other embodiments of the present invention for such purposes:

Carbamic acid, [(2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester;

Carbamic acid, [(2E)-3-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester;

Carbamic acid, [(2E)-3-(4-pyrazinylphenyl)-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester; and

Carbamic acid, [3-[4-(2-pyrimidinyl)phenyl]propyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester.

This invention also provides processes for preparing the instant compounds. The compounds of Formula I may be prepared from readily available starting materials such as erythromycin and erythromycin derivatives well known in the art. Outlined in Schemes 1 through 11 are representative procedures to prepare the compounds of the instant invention:

Scheme 1 illustrates the method of synthesis of the 2′,4″-diacetyl-6-carbamyl-11,12-dideoxy-11,12-iminocarbonyloxyerythromycin A (VI) and the 2′-acetyl-6-carbamyl-11,12-dideoxy-3-O-descladinosyl-11,12-iminocarbonyloxyerythromycin A (1a) precursors to the compounds of the invention.

Erythromycin A is treated with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from −20° C. to 37° C. for 2 to 48 hours to afford 2′,4″,11-triacetylerythromycin A (I). The 10,11-anhydro derivative (II) can be readily obtained by treatment of I with a base in an inert solvent such as THF, dioxane, DME, or DMF at a temperature ranging from −78° C. to 80° C. for 1-24 hours. Suitable bases to effect the elimination reaction include, but are not limited to, sodium hexamethyidisilazide, potassium hexamethyldisilazide, LDA, lithium tetramethylpiperidide, DBU, and tetramethylguanidine. It will be apparent to one skilled in the art that alternative methods for synthesis of 2′,4″-diacetyl-10,11-anhydroerythromycin A are available, including conversion of erythromycin A to the 11,12-cyclic carbonate derivative with ethylene carbonate, followed by elimination with tetramethylguanidine, as described in Hauske, J. R. and Kostek, G., J. Org. Chem. 1982, 47, 1595. Selective protection of the 2′ and 4″-hydroxyl groups can then be readily accomplished with acetic anhydride in the presence of a tertiary amine base. Likewise, alternative protecting group strategies may be employed. For example, erythromycin A may be treated with benzoic anhydride, propionic anhydride, or formic acetic anhydride under similar conditions as described above to obtain the 2′,4″,11-triacylated erythromycin A derivative followed by elimination to afford the corresponding 10,11-anhydro compound.

Once the suitably protected 10,11-anhydro derivative is obtained, derivatization of both tertiary hydroxyl groups can be carried out by treatment with trichloroacetylisocyanate in an inert solvent, such as methylene chloride, chloroform, or THF at a temperature ranging from −20° C. to 37° C. for 1-24 hours to yield the di-(N-trichloroacetyl)carbamate derivative (III). The N-trichloroacetylcarbamate functionalities can be hydrolyzed to the corresponding primary carbamates by treatment with a suitable base, such as triethylamine, in an aqueous solvent mixture, such as methanol/water for 1-24 hours at a temperature ranging from 20° C. to 80° C. Alternative bases may likewise be used to effect this conversion, such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Under the reaction conditions, the primary carbamate formed at the 12-position undergoes spontaneous Michael addition to the electrophilic 11-position of the α,β-unsaturated ketone and the 2′-acetoxy group is hydrolyzed to the corresponding hydroxyl to afford the cyclic carbamate derivative (IV). Compound IV is generally isolated as a mixture of methyl epimers at the C10-position, which can be readily converted to the desired C10-β-methyl epimer (V) by treatment with an equilibrating base, such as potassium t-butoxide, tetramethylguanidine, or DBU in a suitable solvent, such as THF, dioxane, DME, DMF or t-butanol at a temperature ranging from −78° C. to 80° C. for 1 to 24 hours. Reprotection of the 2′-hydroxyl group to give VI can be carried out by treatment with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and optionally an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from −20° C. to 37° C. for 2 to 48 hours. It is understood that an orthogonal protection strategy of the sugar hydroxyls may also be employed by treatment of V with alternate reagents such as benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl chloride. Finally, selective removal of the cladinose sugar can be accomplished by reaction of VI with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water to afford 1a. Reaction time is typically 0.5-24 hours at a temperature ranging from −10° C. to 37° C.

Scheme 2 depicts synthesis of compounds of formulae 1b, 1c and 1d, wherein RCHO is an aldehyde (R may be a member of the group including, but not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkenyl, arylalkynyl, aralkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkynyl, and heterocycloalkyl). Oxidation of the 3-hydroxy group of 1a to yield compound 1b can be effected with DMSO and a carbodiimide, such as EDCl, in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from −20° C. to 37° C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Removal of the 2′-acetyl group of compound 1b is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from −20° C. to 60° C. to yield compound 1c. Alternative methods for deprotection of the 2′-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. Compounds of formula 1d can be obtained by selective alkylation of the primary carbamate of 1c with a suitably substituted aldehyde in the presence of a reducing agent and acid. Alternatively, the corresponding acetal may be used in place of the suitably substituted aldehyde in this reaction. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at −20° C. to 100° C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal.

It will be clear to one skilled in the art that the order of the steps in the synthetic sequence leading to compounds of the invention can be altered, provided that the functionality present in the molecule is compatible with the desired selective transformations. This is illustrated in Scheme 3. For example, compound 1a can be treated under similar conditions as described above for the reductive alkylation of compound 1c (Scheme 2) to yield compounds of the formula 1e. Removal of the 2′-acetyl group of compound 1e as described for the conversion of compound 1b to compound 1c (Scheme 2) provides compounds of formula 1g. Alternatively, oxidation of the 3-hydroxyl of compound 1e to the ketone of compound 1f can be conducted as described for the analogous transformation of 1a to 1b in Scheme 2. Finally, deprotection of the 2′-acetyl group of 1f is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2) to provide the compounds of formula 1d, wherein R is as previously defined.

Scheme 4 illustrates an alternate route for the preparation of the compounds of the invention (1d). Reaction of compound VI with a suitably substituted aldehyde and a reducing agent, such as triethylsilane, in the presence of an acid, such as trifluoroacetic acid, in a suitable solvent, such as acetonitrile, methylene chloride, or toluene, at a temperature ranging from −20° C. to 100° C. for 2-96 hours leads to the simultaneous removal of the cladinose sugar and the selective alkylation of the primary carbamate to afford compound 1e. Alternatively, the corresponding acetal of the suitably substituted aldehyde may be used to effect this transformation. Conversion of compound 1e to compound 1f and compound 1f to compound 1d can be conducted as described above.

Scheme 5, wherein R^(4a) is halogen and R is as described above, illustrates the procedures by which compounds of formula 1b can be converted to compounds of formula 1j.

Fluorination of compound 1b can be accomplished with any one of a number of fluorinating reagents, including N-fluorobenzenesulfonimide in the presence of base, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis[tetrafluoroborate] (SELECTFLUOR™) in the presence of base, 10% F₂ in formic acid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate, 3,5-dichloro-1-fluoropyridinium triflate, (CF₃SO₂)₂NF, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base, N-fluoropyridinium triflate, and N-fluoroperfluoropiperidine in the presence of base to give 1h wherein R^(4a) is F. Chlorination of 1b can be effected with hexachloroethane in the presence of base, sulfuryl chloride, thionyl chloride, trifluoromethanesulfonyl chloride in the presence of base, chlorine, or sodium hypochlorite in the presence of acetic acid to give 1h wherein R^(4a) is Cl. Suitable brominating agents would include pyridinium hydrobromide perbromide, bromine in acetic acid, N-bromosuccinimide in the presence of base, 1,2-dibromoethane in the presence of base, or carbon tetrabromide in the presence of base to give 1h wherein R^(4a), is Br. Suitable iodinating agents include N-iodosuccinimide in the presence of base or iodine to give 1h wherein R^(4a) is l.

Transformation of the halogenated derivatives 1h to the corresponding compounds of formula 1j can be accomplished through analogous synthetic routes as above. Reaction of 1h with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid yields compounds 1i. Reagent combinations for effecting this transformation include triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at −20° C. to 100° C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds 1i are then converted to the corresponding compounds of formula 1j by reaction with methanol for 2-48 hours at a temperature ranging from −20° C. to 60° C.

It will be understood by one skilled in the art of organic synthesis that the halogenation reaction can also be conducted at a later stage in the synthetic sequence. For example, halogenation of compound 1f (Scheme 3) affords the corresponding 2-halo derivative, which likewise can be converted to compounds of the invention by deprotection of the 2′-acetyl group under the previously described conditions.

Schemes 6A and 6B illustrate the procedures by which compounds of the formula 1b can be converted to 2α- and 2β-fluoro derivatives of formulae 1n and 1q. Fluorination of compound 1b can be accomplished as described herein above. Reagent combinations for the conversion of compound 1b to the 2α-fluoro derivative 1k include SELECTFLUOR and sodium hexamethyldisilazide in DMF and N-fluorobenzenesulfonimide and potassium t-butoxide in THF. Typically, the reaction is conducted at −78° C. to −60° C. for 5 minutes to 24 hours. Reagent combinations for the conversion of compound 1b to the 2β-fluoro derivative 1o include N-fluorobenzenesulfonimide and sodium hydride in DMF. Typically, this reaction is conducted at 0° C. to 20° C. for 1 to 24 hours.

Transformation of the fluorinated derivatives 1k and 1o to the corresponding compounds of the invention 1n and 1q, respectively, can be accomplished through analogous synthetic routes as above. Reaction of 1k or 1o with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid yields compounds 1m and 1p, respectively. Reagent combinations for effecting this transformation include triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at −20° C. to 100° C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds 1m and 1p are then converted to the corresponding compounds of the invention 1n and 1q, respectively, by reaction with methanol for 2-48 hours at a temperature ranging from −20° C. to 60° C.

It will be also understood by one skilled in the art of organic synthesis that the fluorination reaction can also be conducted at a later stage in the synthetic sequence. For example, fluorination of compound 1f (Scheme 3) affords the corresponding 2-fluoro derivative, which likewise can be converted to compounds of the invention by deprotection of the 2′-acetyl group under the previously described conditions.

Other compounds of the invention may also be suitable substrates for further transformation to yield other compounds of the present invention. Some of these transformations are illustrated in Schemes 7-11.

Scheme 7 illustrates the conversion of the 3-(4-nitrophenyl)-2-propenyl analog (1r) to the 3-[4-(4H-1,2,3-triazol-4-yl)phenyl]-2-propenyl analog (1t) via the intermediacy of the 3-(4-aminophenyl)-2-propenyl derivative (1s) wherein R⁴ is as described above. The selective reduction of the nitro group of 1r to the amine of 1s can be conducted with tin(II) chloride in ethanol at a temperature ranging from 20° C. to 78° C., typically for 1 to 24 hours. Alternative methods for reduction of the nitro group can also be employed, including iron/hydrochloric acid, iron/acetic acid, tin/hydrochloric acid, zinc/ammonium chloride, or sodium borohydride/nickel chloride. Conversion of the amino group of 1s to the 1,2,4-triazole of 1t is effected by condensation of the amine with N,N-dimethylformamide azine dihydrochloride in the presence of a base, such as pyridine. Reaction time is typically 2 to 72 hours at a temperature ranging from −20° C. to 115° C.

Scheme 8 depicts the conversion of 3-(4-bromophenyl)-2-propenyl analog (1u) to the 3-(1,1′-biphen-4-yl)-2-propenyl analog (1v) wherein R₄ is as described above. Reaction of the aryl bromide with an aryl boronic acid derivative to give the biaryl derivative is conducted under typical Suzuki coupling conditions, i.e., in the presence of a Pd⁰ catalyst, typically palladium tetrakistriphenylphosphine, and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20° C. to 110° C. Aryl iodides and aryl triflates are also suitable substrates for this conversion.

Scheme 9 illustrates the conversion of a substituted N-propenylcarbamate derivative (1w) to the corresponding substituted N-propylcarbamate compound (1x), wherein R′ may be a member of the R group except alkenyl and alkynyl, and R and R⁴ is as described above. Typically, this transformation is conducted via catalytic transfer hydrogenation, in which the olefin is reacted with ammonium formate in the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as methanol or ethanol, at a temperature ranging from 20° C. to 60° C. for 15 minutes to 24 hours. Other methods for reduction of the double bond could also be applicable, for example treatment with hydrogen in the presence of a noble metal catalyst, such as palladium or platinum. It will be obvious to one skilled in the art that the analogous N-propynylcarbamate may likewise be reduced to the corresponding N-propylcarbamate under similar conditions.

Scheme 10 illustrates a method for conversion of a secondary carbamate derivative (1j) to a tertiary carbamate derivative (1y), wherein R″ is an independent member of the R group, and R and R⁴ are as described above, by reaction with an aldehyde and a suitable reducing agent, typically triethylsilane, in the presence of an acid, typically trifluoroacetic acid, in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene. Reaction times are typically 2 to 96 hours at a temperature ranging from 20° C. to 110° C. Alternative methods for effecting this conversion may also be contemplated, for example reaction of a suitably protected secondary carbamate precursor with an alkyl halide in the presence of a sufficiently strong base, such as sodium hydride, potassium hexamethyldisilazide, or LDA.

Scheme 11 illustrates the conversion of compounds 1d, wherein R is as previously defined, to compounds containing a 2-hydroxy substituent (1z). This transformation may be conducted by treatment of compound 1d with charcoal in the presence of air in a suitable solvent, such as methanol or ethanol. It will be apparent to one skilled in the art of organic synthesis that other methods may be employed to effect this conversion, including for example treatment of 1d with a base, such as potassium hexamethyidisilazide or LDA, and an oxidant, such as camphorsulfonyloxaziridine or MoOPh.

Scheme 12 illustrates the conversion of 1a′ to compounds of the invention 1b′, 1c′, 1d′, 1e′, 1f′, and 1g′ with a nitrogen-containing substituent on the carbamate in the 6-position, wherein R⁴ and R_(a) are as described above. Reaction of 1a′ with a protected aminoaldehyde derivative, such as N-(benzyloxycarbonyl)glycinal, in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid affords the protected amine derivative (1b′). Typically this reaction is conducted in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene, for 2 to 96 hours at a temperature ranging from 20° C. to 110° C. Deprotection of 1b′ to afford the corresponding amine derivative (1c′) can be readily effected by procedures known in the art, such as catalytic hydrogenation in the presence of a noble metal catalyst or catalytic transfer hydrogenation with palladium on carbon in the presence of cyclohexadiene or ammonium formate at a temperature ranging from 20° C. to 60° C. Typically these reactions are conducted in an inert solvent such as methanol or ethanol. Conversion of 1c′ to several of the compounds of the invention (Scheme 12) can be conducted with techniques known in the art, such as reductive alkylation with formaldehyde in the presence of a suitable reducing agent, such as sodium cyanoborohydride, and an acid, such as acetic acid to afford the alkylated amine derivative (1d′). Alternatively, 1c′ may be converted to the amide derivative (1e′) by acylation with a suitably substituted acid chloride or acid anhydride in the presence of a base, such as pyridine, optionally in the presence of an acylation catalyst, such as DMAP. Amine derivative (1c′) may also converted to a carbamate (1f′) by treatment with a suitably substituted chloroformate or pyrocarbonate derivative in the presence of pyridine. Finally, reaction of 1c′ with a suitably substituted isocyanate in an inert solvent, such as tetrahydrofuran or methylene chloride, provides access to the correponding urea derivatives (1g′). Optional deprotection of the 2′-acetyl group of 1b′, 1c′, 1d′, 1e′, 1f′, and 1g′ is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2).

Scheme 13 illustrates the analogous procedure whereby 1a′ is converted to compounds of the invention 1h′, 1i′, 1j′, and 1k′ with a carbonyl-containing substituent on the carbamate in the 6-position, wherein R⁴ and R_(a) are as described above. Reaction of 1a′ with, for example, benzyl 4-oxobutanoic acid (Cannon, J. G. and Garst, J. E., J. Org. Chem. 1975, 40, 182) in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid affords the benzyl ester derivative (1h′). Typically this reaction is conducted in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene, for 2 to 96 hours at a temperature ranging from 20° C. to 110° C. Deprotection of 1h′ to afford the corresponding acid derivative (1i′) can be readily effected by procedures known in the art, such as catalytic hydrogenation in the presence palladium on carbon in an inert solvent such as methanol or ethanol. Conversion of 1i′ to other compounds of the invention (Scheme 13) can be executed with techniques known in the art, such as reaction with a suitably substituted alcohol or amine in the presence of a coupling agent such as dicyclohexylcarbodiimide, BOP, or PyBOP, optionally in the presence of a base, such as diisopropylethylamine, and an acylation catalyst, such as DMAP or HOAt, to afford the corresponding ester derivative (1j′) or amide derivative (1k′). Optional deprotection of the 2′-acetyl group of 1h′, 1i′, 1j′, and 1k′ is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2).

When the aldehydes or acetals used in the preparation of compounds 1d, 1e, 1i, 1m, 1p, and 1y are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions. Exemplary syntheses of several of the aldehydes used in the preparation of 1d, 1e, 1i, 1m, 1p, and 1y are presented hereinafter as reference examples.

Compounds of the invention wherein R³ is a group other than H may be prepared as described in WO 98/25942.

Compounds of the invention wherein R⁵ is a hydroxy protecting group other than acyl may be prepared in methods analogous to those shown in the above schemes with appropriate reagents that are either commercially available or may be made by known methods.

Compounds of the invention wherein R⁶ is a group other than ethyl may be prepared beginning with modified erythromycin derivatives as starting materials as described in various publications including, but not limited to, WO99/35157, WO00/62783, WO00/63224, and WO00/63225.

These compounds have antimicrobial activity against susceptible and drug resistant Gram positive and Gram negative bacteria. In particular, they are useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly activity against S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococci, Moraxella catarrhalis and H. influenzae. These compounds are particularly useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.

Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol.17, No.2, “Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically—Fourth Edition”, which is incorporated herein by reference.

In this method two-fold serial dilutions of drug in cation adjusted Mueller-Hinton broth are added to wells in microdilution trays. The test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5×10⁴ CFU/well.

Following inoculation of the microdilution trays, the trays are incubated at 35° C. for 16-20 hours and then read. The MIC is the lowest concentration of test compound that completely inhibits growth of the test organism. The amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray. As set forth in Table 1, compounds of the present invention were tested against a variety of Gram positive and Gram negative pathogenic bacteria resulting in a range of activities depending on the organism tested.

Table 1 below sets forth the biological activity (MIC, μg/mL) of some compounds of the present invention.

TABLE 1 MIC Values (μg/mL) of Some Compounds of Formula I No. A B C D E 1 >16 4 0.12 0.03 ND 2 16 1 0.25 0.06 2 3 >16 4 1 0.12 8 4 >16 0.25 0.12 0.03 1 5 >16 0.5 0.25 0.03 ND 6 >16 4 1 0.12 ND 7 16 0.5 0.06 0.03 4 8 16 1 0.12 0.03 4 9 >16 1 0.25 0.03 16 10 16 1 0.25 0.03 4 11 >16 4 2 0.5 >16 12 16 1 0.12 0.06 4 13 >16 1 0.25 0.06 8 14 >16 8 0.5 0.12 >16 15 4 0.12 0.06 0.03 2 16 8 0.5 0.12 0.03 4 17 16 0.5 0.25 0.06 4 18 16 0.25 0.06 0.03 4 19 16 0.12 0.12 0.03 4 20 16 0.12 0.06 0.03 4 21 >16 0.5 0.25 0.06 4 22 8 0.25 0.06 0.03 2 23 16 0.25 0.12 0.06 2 24 16 1 0.12 0.06 2 25 8 0.25 0.06 0.03 4 26 >16 0.5 0.12 0.03 2 27 16 0.25 0.12 0.06 4 28 16 0.25 0.06 0.03 4 29 16 0.5 0.06 0.03 2 30 16 0.5 0.12 0.03 2 31 16 0.25 0.06 0.03 2 32 16 0.12 0.06 0.06 ND 33 8 0.12 0.06 ≦0.015 ND 34 8 0.12 0.06 ≦0.015 ND 35 8 0.12 0.03 ≦0.015 ND 36 8 0.12 0.03 ≦0.015 ND 37 16 0.5 0.12 0.03 ND 38 8 0.12 0.03 ≦0.015 ND 39 >16 1 0.12 0.06 1 40 16 1 0.5 0.12 ND 41 16 0.25 0.12 0.03 1 42 16 0.5 0.12 0.12 1 43 >16 0.25 0.12 0.03 2 44 >16 0.25 0.12 0.12 2 45 >16 1 0.5 0.25 4 46 16 0.25 0.06 ND 2 47 16 0.25 0.06 ND 1 48 >16 0.5 0.12 ND 4 49 16 0.25 0.06 0.06 2 50 16 0.25 0.06 <0.015 2 51 >16 0.5 0.12 0.06 8 52 8 0.25 0.12 0.03 2 53 16 0.25 0.12 0.03 4 54 >16 1 0.5 0.12 2 55 16 0.5 0.12 0.03 4 56 8 0.25 0.06 ≦0.015 2 57 16 0.25 0.12 0.03 2 58 >16 0.25 0.12 0.06 4 59 >16 0.5 <0.25 0.03 4 60 >16 1 0.5 0.25 8 61 16 0.5 0.06 0.03 2 62 >16 0.25 0.12 0.06 4 63 >16 0.25 0.12 0.06 2 64 >16 1 0.12 0.03 4 65 >16 2 0.25 0.06 8 66 >16 0.5 0.12 0.06 4 67 >16 0.25 0.25 0.06 4 68 >16 0.25 0.12 0.03 4 69 >16 0.5 0.12 0.03 8 70 16 0.25 0.12 0.03 4 71 >16 0.25 0.12 0.06 4 72 8 0.25 0.06 ≦0.015 2 73 16 0.5 0.06 0.03 2 74 16 0.06 0.06 ≦0.015 1 75 >16 0.25 0.12 0.03 4 76 16 0.25 0.06 ≦0.015 2 77 16 0.12 0.12 0.03 4 78 >16 0.25 0.06 0.03 4 79 8 0.25 0.06 0.03 2 80 >16 0.12 0.06 0.03 4 81 >16 2 0.12 0.06 8 82 >16 0.25 0.06 0.03 4 83 >16 2 0.25 0.06 8 84 >16 0.25 0.12 0.06 4 85 >16 1 0.25 0.12 >16 86 >16 0.5 0.12 0.06 8 87 16 0.25 0.06 0.03 4 88 16 0.25 0.06 0.06 8 89 16 0.5 0.25 0.06 8 90 8 0.25 0.06 0.03 4 91 16 0.25 0.12 0.06 4 92 16 0.25 0.12 0.03 2 93 16 0.5 0.06 ≦0.015 1 94 >16 0.25 0.12 0.06 2 95 >16 1 0.25 ND 2 96 4 0.25 0.12 0.03 1 97 16 0.5 0.06 0.03 2 98 >16 0.5 0.25 0.03 4 99 8 0.5 0.12 ND 1 100 16 0.5 0.12 ND 2 101 8 0.25 0.12 0.03 2 107 >16 0.25 0.12 0.06 4 108 >16 0.5 0.25 0.06 4 (A: E. coli OC2605; B: S. aureus ATCC29213; C: E. faecalis ATCC29212; D: S. pneumoniae ATCC49619; E: H. influenzae ATCC49247)

This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.

When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.

Compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.

In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, which may be given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 2000 mg. Dosage forms suitable for internal use comprise from about 100 mg to 1200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).

The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could increase the yields.

EXAMPLE 1 Compound 6 (Formula 1′: R₁ is H, R₂ is H, R₃ is H, R₄ is H)

Step A

Triethylamine (42.0 mL, 301 mmol), DMAP (0.6 g, 4.9 mmol), and acetic anhydride (28.5 mL, 302 mmol) were added to a 0° C. suspension of erythromycin (36.7 g, 50 mmol) in dichloromethane (250 mL). The mixture was allowed to warm to room temperature and stir for 18 h. Methanol (10 mL) was added and stirring was continued for 5 min. The mixture was diluted with ether (750 mL), washed with sat. aq. NaHCO₃, water, and brine (500 mL each), dried (MgSO₄), and concentrated to provide the title compound as a colorless foam. The material was used in the next step without further purification. MS 860 (M+H)⁺.

Step B

Sodium hexamethyldisilazide (1.0M in THF, 60.0 mL, 60.00 mmol) was added over 25 min to a 0° C. solution of the compound from step A (50.0 mmol) in THF (500 mL). After 2 h at 0° C., the mixture was diluted with water (250 mL) and brine (250 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layers were dried (MgSO₄) and concentrated. The material was used in the next step without further purification. If desired, pure material could be obtained by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH). MS 800 (M+H)⁺.

Step C

Trichloroacetylisocyanate (18.0 mL, 151 mmol) was added over 20 min to a 0° C. solution of the compound from step B (50 mmol) in dichloromethane (350 mL). After 3 h at 0° C., the reaction was quenched by the addition of methanol (30 mL) and concentrated. The residue was dissolved in a mixture of methanol (450 mL), water (45 mL), and triethylamine (18 mL), heated to reflux for 2 h, and concentrated. The residue was dissolved in ethyl acetate (500 mL), washed with sat. aq. NaHCO₃ (250 mL) and brine (250 mL), dried (MgSO₄), and concentrated. The resulting mixture of C-10 epimers was dissolved in THF (500 mL) at 0° C. and potassium t-butoxide (1.0 M in THF, 60.0 mL, 60.0 mmol) was added over 15 min. The resulting mixture was stirred at 0° C. to 15° C. for 6 h. Sat. aq. NaHCO₃ (250 mL) was added, the bulk of the THF was removed in vacuo, and the resulting solution was extracted with ethyl acetate (3×250 mL). The combined organic extracts were washed with brine (250 mL), dried (MgSO₄), and concentrated. The material was used in the next step without further purification. If desired, pure material could be obtained by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH). MS 844 (M+H)⁺.

Step D

A solution of the compound from step C (50 mmol), triethylamine (13.0 mL, 93.3 mmol), and acetic anhydride (8.8 mL, 93.3 mmol) in dichloromethane (250 mL) was stirred at room temperature for 20 h. The solution was washed with sat. aq. NaHCO₃ (2×250 mL) and brine (250 mL), dried (MgSO₄), and concentrated. The material was used in the next step without further purification. MS 886 (M+H)⁺.

Step E

The compound from step D (50 mmol) was dissolved in 1.2 N HCl (400 mL) and ethanol (160 mL) and stirred at room temperature for 20 h. The mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.5 dichloromethane/methanol/conc. NH₄OH) yields 10.4 g (30% based on erythromycin) of the title compound as a colorless solid. MS 686 (M+H)⁺.

Step F

EDCl (3.92 g, 20.45 mmol) was added to a solution of the compound from step E (2.00 g, 2.92 mmol) and dimethyl sulfoxide (3.70 mL, 52.14 mmol) in dichloromethane (10 ml) at 0° C. A solution of pyridinium trifluoroacetate (3.94 g, 20.40 mmol) in dichloromethane (10 mL) was added over 10 min and the resulting solution was stirred at 0° C. for 2 h before being quenched with water (2 mL). After 5 min, the mixture was diluted with dichloromethane (50 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. The material was used in the next step without further purification. If desired, pure material could be obtained by chromatography (SiO₂, 96:4:0.2 dichloromethane/methanol/conc. NH₄OH). MS 684 (M+H)⁺.

Step G

The crude product from step F was allowed to stand in methanol (20 mL) for 24 h and then concentrated. Purification by chromatography (SiO₂, 94:6:0.2 dichloromethane/methanol/conc. NH₄OH) yields 1.39 g (74%) of the title compound as a colorless solid. MS 642 (M+H)⁺.

EXAMPLE 2 Compound 106 (Formula 1′: R₁ is H, R₂ is H, R₃ is H, R₄ is F)

Sodium hexamethyldisilazide (1.0M in THF, 1.14 mL, 1.14 mmol) was added to a solution of the compound from Example 1, step F (520 mg, 0.76 mmol) in DMF (8 mL) at −60° C. After 30 min at −60° C., SELECTFLUOR™ (324 mg, 0.91 mmol) was added. The resulting mixture was stirred for 10 min at −60° C., diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), and concentrated. This material was allowed to stand in methanol for 24 h and then concentrated. Purification by chromatography (SiO₂, 3-5% methanol in dichloromethane+0.1% conc. NH₄OH) followed by a second chromatography (SiO₂, acetone) yielded 201 mg (40%) of the title compound. MS 660 (M+H)⁺.

EXAMPLE 3 2′-Acetate of Compound 106

Potassium t-butoxide (1.0 M in THF, 0.23 mL, 0.23 mmol) was added dropwise to a −78° C. solution of the compound from Example 1, step f (120 mg, 0.18 mmol) in THF (3 mL). After 30 min at −78° C., N-fluoro benzensulfonimide (72 mg, 0.23 mmol) was added and the mixture was stirred at −78° C. for 4 h. Sat. aq. NaHCO₃ was added, the mixture was stirred for 10 min, and then extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 36 mg (29%) of the title compound. MS 702 (M+H)⁺.

EXAMPLE 4 Compound 1 (Formula 1′: R₁ is Phenylmethyl, R₂ is H, R₃ is H, R₄ is H)

Step A

A solution of the compound from Example 1, step E (100 mg, 0.15 mmol), triethylsilane (116 μL, 0.73 mmol), trifluoroacetic acid (54 μL, 0.70 mmol), and benzaldehyde (74 μL, 0.73 mmol) in CH₃CN (0.5 mL) was stirred at room temperature for 18 h and then heated to 60° C. for 22 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (5 mL) and brine (5 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 72 mg (64%) of the title compound. MS 776 (M+H)⁺.

Step B

The Dess-Martin reagent (75 mg, 0.18 mmol) was added to a solution of the product from step A (68 mg, 0.088 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature for 8 h. The solvent was evaporated and the residue was diluted with ethyl acetate (10 mL), washed with 1:1 sat aq. NaHCO₃/10% Na₂S₂O₃ (10 mL), water (5 mL), and brine (5 mL), dried (Na₂SO₄), and concentrated. The material obtained was stirred in methanol (3 mL) for 24 h and then concentrated. Purification by chromatography (SiO₂, 96:4:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 31 mg (48%) of the title compound. MS 732 (M+H)⁺.

EXAMPLE 5 Compound 2 (Formula 1′: R₁ is 3-phenylpropyl, R₂ is H, R₃ is H, R₄ is H)

Step A

A solution of the compound from example 1, step E (250 mg, 0.37 mmol), triethylsilane (290 μL, 1.82 mmol), trifluoroacetic acid (135 μL, 1.75 mmol), and hydrocinnamaldehyde (240 μL, 1.82 mmol) in CH₃CN (1.5 mL) was heated to 60° C. for 3 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (15 mL), 10% aq. NaHSO₃ (15 mL), and brine (15 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 212 mg (74%) of the title compound. MS 804 (M+H)⁺.

Step B

The Dess-Martin reagent (169 mg, 0.40 mmol) was added to a solution of the product from step A (160 mg, 0.20 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 24 h. The solvent was evaporated and the residue was diluted with ethyl acetate (30 mL), washed with 1:1 sat aq. NaHCO₃/10% Na₂S₂O₃ (15 mL), water (15 mL), and brine (15 mL), dried (MgSO₄), and concentrated. The material obtained was stirred in methanol (6 mL) for 24 h and then concentrated. Purification by chromatography )SIO₂,96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 52 mg (34%) of the title compound. MS 760 (M+H)⁺.

EXAMPLE 6 Compound 3 (Formula 1′: R₁ is 2-Phenylethyl, R₂ is H, R₃ is H, R₄ is H)

Step A

A solution of the compound from example 1, step E (100 mg, 0.15 mmol), triethylsilane (116μL, 0.73 mmol), trifluoroacetic acid (54 μL, 0.70 mmol), and phenylacetaldehyde (74 μL, 0.73 mmol) in CH₃CN (0.5 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (5 mL) and brine (5 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 93 mg (81%) of the title compound. MS 790 (M+H)⁺.

Step B

The Dess-Martin reagent (150 mg, 0.36 mmol) was added to a solution of the product from step a (93 mg, 0.12 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 24 h. The solvent was evaporated and the residue was diluted with ethyl acetate (30 mL), washed with 1:1 sat aq. NaHCO₃/10% Na₂S₂O₃(15 mL), water (15 mL), and brine (15 mL), dried (MgSO₄), and concentrated. The material obtained was stirred in methanol (6 mL) for 24 h and then concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 42 mg (48%) of the title compound. MS 746 (M+H)⁺.

EXAMPLE 7 Compound 4 (Formula 1′: R₁ is (2E)-3-Phenyl-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step F (90 mg, 0.13 mmol), triethylsilane (105μL, 0.66 mmol), trifluoroacetic acid (50 μL, 0.65 mmol), and cinnamaldehyde (85μL, 0.67 mmol) in CH₃CN (0.5 mL) was stirred at room temperature for 5 days. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. The product was owed to stand in methanol (3 mL) for 24 h and concentrated. Purification by chromatography (SiO₂, 97:3:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 50 mg (50%) of the title compound as a colorless solid. MS 758 (M+H)⁺.

EXAMPLE 8 Compound 5 (Formula 1′: R₁ is (4-Bromophenyl)methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (500 mg, 0.78 mmol), triethylsilane (0.63 mL, 3.94 mmol), trifluoroacetic acid (0.30 mL, 3.89 mmol), and 4-bromobenzaldehyde (720 mg, 3.89 mmol) in CH₃CN (2.0 mL) was heated to 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (30 mL) and brine (30 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.5 dichloromethane/methanol/conc. NH₄OH) yielded 500 mg (79%) of the title compound as a colorless solid. MS 810 (M+H)⁺.

EXAMPLE 9 Compound 7 (Formula 1′: R₁ is [4-(1H-Pyrazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and 4-(1H-pyrazol-1-yl)-benzaldehyde (134 mg, 0.78 mmol, prepared as described in J. Med Chem. 1998, 41, 2390) in CH₃CN (1.0 mL) was heated to 62 ° C. for 3 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 102 mg (82%) of the title compound. MS 798 (M+H)⁺.

EXAMPLE 10 Compound 8 (Formula 1′: R₁ is [4-(1H-Imidazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (200 μL, 1.25 mmol), trifluoroacetic acid (96 μL, 1.25 mmol), and 4-(1H-imidazol-1-yl)-benzaldehyde (108 mg, 2 mmol, prepared as described in J. Med Chem. 1998, 41, 2390) in CH₃CN (1.0 mL) was heated to 65° C. for 4 days. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 8.3 mg (8%) of the title compound. MS 798 (M+H)⁺.

EXAMPLE 11 Compound 9 (Formula 1′: R₁ is 4-Phenylbutyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (50 μL, 0.65 mmol), and the compound from Reference Example 1 (93 mg, 0.62 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 48 mg (50%) of the title compound. MS 774 (M+H)⁺.

EXAMPLE 12 Compound 10 (Formula 1′: R₁ is [4-(1H-1,2,4-Triazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (48 μL, 0.62 mmol), and 4-(1H-1,2,4-triazol-1-yl)-benzaldehyde (108 mg, 0.62 mmol, prepared as described in J. Med Chem. 1998, 41, 2390) in CH₃CN (1.0 mL) was heated to 65° C. for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 78 mg (78%) of the title compound. MS 799 (M+H)⁺.

EXAMPLE 13 Compound 11 (Formula 1′: R₁ is 3-Phenyl-2-propynyl, R₂ is 3-Phenyl-2-propynyl, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (48 μL, 0.62 mmol), and phenylpropargyl aldehyde (81 mg, 0.62 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 73 mg (67%) of the title compound. MS 870 (M+H)⁺.

EXAMPLE 14 Compound 12 (Formula 1′: R₁ is 3-(3-Pyridinyl)propyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (50 μL, 0.65 mmol), and 3-pyridinepropanal (84 mg, 0.62 mmol, prepared as described in Bull. Chem. Soc. Jpn. 1997, 70, 3061) in CH₃CN (1.0 mL) was heated to 60° C. for 24 h. Additional triethylsilane (100 μL, 0.62 mmol) and trifluoroacetic acid (50 μL, 0.65 mmol) was added and heating at 60° C. was continued for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 58 mg (61%) of the title compound. MS 761 (M+H)⁺.

EXAMPLE 15 Compound 13 (Formula 1′: R₁ is 3-Phenyl-2-propynyl, R₂ is H, R₃ is H, R₄is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (50 μL, 0.65 mmol), and phenylpropargyl aldehyde (81 mg, 0.62 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 25 min. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 18 mg (19%) of the title compound. MS 756 (M+H)⁺.

EXAMPLE 16 Compound 14 (Formula 1′: R₁ is 3-[4-(Dimethylamino)phenyl]propyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (48 μL, 0.62 mmol), and 4-(dimethylamino)cinnamaldehyde (110 mg, 0.62 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 38 mg (38%) of the title compound. MS 803 (M+H)⁺.

EXAMPLE 17 Compound 15 (Formula 1′: R₁ is (2E)-3-(4-Nitrophenyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (48 μL, 0.62 mmol), and 4-nitrocinnamaldehyde (111 mg, 0.62 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 62 mg (67%) of the title compound. MS 803 (M+H)⁺.

EXAMPLE 18 Compound 16 (Formula 1′: R₁ is (2E)-3-(4-Bromophenyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (256 mg, 0.40 mmol), triethylsilane (320 μL, 2.00 mmol), trifluoroacetic acid (160 μL, 2.08 mmol), and 4-bromocinnamaldehyde (422 mg, 2.00 mmol, prepared as described in Tetrahedron 1998, 54, 10761) in CH₃CN (3.0 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 156 mg (47%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 19 Compound 18 (Formula 1′: R₁ is (2E)-3-[4-(1 H-Pyrazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 30 (154 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 92 mg (72%) of the title compound. MS 824 (M+H)⁺.

EXAMPLE 20 Compound 19 (Formula 1′: R₁ is (2E)-3-[4-(2-Pyridinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 32 (163 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 36 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 82 mg (63%) of the title compound. MS 835 (M+H)⁺.

EXAMPLE 21 Compound 20 (Formula 1: R₁ is (2E)-3-[4-(1H-1,2,4-Triazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 35 (155 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 96 mg (75%) of the title compound. MS 825 (M+H)⁺.

EXAMPLE 22 Compound 21 (Formula 1′: R₁ is (2E)-2-Methyl-3-phenyl-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (125 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and α-methyl-trans-cinnamaldehyde (110 μL, 0.79 mmol) in CH₃CN (0.5 mL) was stirred at room temperature for 40 h and then heated to 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 46 mg (38%) of the title compound as an off-white solid. MS 772 (M+H)⁺.

EXAMPLE 23 Compound 22 (Formula 1′: R₁ is (2E)-3-[4-(1H-Imidazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (150 mg, 0.23 mmol), triethylsilane (186 μL, 1.169 mmol), trifluoroacetic acid (90 μL, 1.169 mmol), and the compound from Reference Example 37 (232 mg, 1.169 mmol) in CH₃CN (1.5 mL) was heated at 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography SIO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 28 mg (15%) of the title compound. MS 824 (M+H)⁺.

EXAMPLE 24 Compound 23 (Formula 1′: R₁ is (2E)-3-[4-(3-Pyridinyl)phenyl]-2-propenyl, R₂ s H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 24 (163 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 39 mg (30%) of the title compound. MS 835 (M+H)⁺.

EXAMPLE 25 Compound 24 (Formula 1′: R₁ is 3-(4-Pyridinyl)propyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.56 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 2 (105 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 26 mg (24%) of the title compound. MS 761 (M+H)⁺.

EXAMPLE 26 Compound 25 (Formula 1′: R₁ is 3-(4-Quinolinyl)propyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and 4-quinolinepropanal (145 mg, 0.78 mmol, prepared as described in J. Med Chem. 1998, 41, 1660) in CH₃CN (1.0 mL) was heated to 60° C. for 18 h. Additional trifluoroacetic acid (60 μL, 0.78 mmol was added and heating at 60° C. was continued for 24 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 20 mg (16%) of the title compound as a brown solid. MS 811 (M+H)⁺.

EXAMPLE 27 Compound 26 (Formula 1′: R₁ is (2E)-3-[4-(4-Pyridinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 33 (163 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 106 mg (82%) of the title compound. MS 835 (M+H)⁺.

EXAMPLE 28 Compound 27 (Formula 1′: R₁ is (2E)-3-[4-(5-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (60 mg, 0.093 mmol), triethylsilane (150 μL, 0.94 mmol), trifluoroacetic acid (72 μL, 0.94 mmol), and the compound from Reference Example 34 (98 mg, 0.47 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 36 mg (46%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 29 Compound 28 (Formula 1′: R₁ is [4-(5-Pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and 4-(5-pyrimidinyl)-benzaldehyde (144 mg, 0.78 mmol, prepared as described in WO 9828264) in CH₃CN (1.0 mL) was heated at 60° C. for 5 days. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 11 mg (9%) of the title compound. MS 810 (M+H)⁺.

EXAMPLE 30 Compound 29 (Formula 1′: R₁ is 3-(3-Quinolinyl)-2-propynyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (80 mg, 0.12 mmol), triethylsilane (100 μL, 0.62 mmol), trifluoroacetic acid (46 μL, 0.62 mmol), and the compound from Reference Example 21 (113 mg, 0.62 mmol) in dichloromethane (1.0 mL) was heated at 50° C. for 6 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 36 mg (36%) of the title compound. MS 807 (M+H)⁺.

EXAMPLE 31 Compound 30 (Formula 1′: R₁ is (2E)-3-(4-Pyridinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and β-(4-pyridyl)acrolein oxalate (175 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 18 h. Additional trifluoroacetic acid (60 μL, 0.78 mmol) and triethylsilane (125 μL, 0.78 mmol) were added and heating at 60° C. was continued for 24 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 40 mg (34%) of the title compound as an off-white solid. MS 759 (M+H)⁺.

EXAMPLE 32 Compound 31 (Formula 1′: R₁ is [4-(2-Pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and 4-(2-pyrimidinyl)-benzaldehyde (144 mg, 0.78 mmol, prepared as described in WO 9828264) in CH₃CN (1.0 mL) was heated at 60° C. for 5 days. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 38 mg (30%) of the title compound. MS 810 (M+H)⁺.

EXAMPLE 33 Compound 32 (Carbamic Acid, [(2E)-3-[4-(2-Pyrimidinyl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-Ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl Ester; (Formula 1′: R₁ is (2E)-3-[4-(2-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 29 (170 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 62 mg (48%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 34 Compound 33 (Formula 1′: R₁ is (2E)-3-[4-(1H-1,2,3-Triazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 36 (160 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 63 mg (49%) of the title compound. MS 825 (M+H)⁺.

EXAMPLE 35 Compound 34 (Formula 1′: R₁ is (2E)-3-(4-Quinolinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 38 (143 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 62 mg (49%) of the title compound. MS 809 (M+H)⁺.

EXAMPLE 36 Compound 35 (Formula 1′: R₁ is [3-(1H-Pyrazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 3 (155 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 86 mg (67%) of the title compound. MS 824 (M+H)⁺.

EXAMPLE 37 Compound 36 (Formula 1′: R₁ is (2E)-3-[3-(2-Pyridinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 39 (163 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 46 mg (35%) of the title compound. MS 835 (M+H)⁺.

EXAMPLE 38 Compound 37 (Formula 1′: R₁ is [3-(2-Pyridinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 11 (146 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 6 days. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 38 mg (35%) of the title compound. MS 809 (M+H)⁺.

EXAMPLE 39 Compound 38 (Formula 1′: R₁ is (2E)-3-(6-Quinolinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 28 (145 mg, 0.79 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 18 h. Additional trifluoroacetic acid (60 μL, 0.78 mmol) was added and heating at 60° C. was continued for 24 h. A third portion of trifluoroacetic acid (60 μL, 0.78 mmol) was added and heating at 60° C. was continued for 24 h. The reaction mixture was diluted with ethyl acetates (15 mL), washed with sat. aq. NaHCO₃(10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.4 dichloromethane/methanol/conc. NH₄OH) yielded 49 mg (39%) of the title compound as a yellow solid. MS 809 (M+H)⁺.

EXAMPLE 40 Compound 39 (Formula 1′: R₁ is [4-(1H-Pyrazol-3-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and 4-(1H-pyrazol-3-yl)benzaldehyde (136 mg, 0.78 mmol, prepared as described in J. Med. Chem. 1998, 41, 2390) in CH₃CN (1.0 mL) was heated at 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 80 mg (65%) of the title compound. MS 798 (M+H)⁺.

EXAMPLE 41 Compound 41 (Formula 1′: R₁ is (2E)-3-(6-Quinoxalinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 27 (145 mg, 0.79 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 20 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 69 mg (55%) of the title compound as a brown solid. MS 810 (M+H)⁺.

EXAMPLE 42 Compound 42 (Formula 1′: R₁ is [4-(5-Nitro-2-pyridinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 19 (178 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 36 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 40 mg (30%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 43 Compound 43 (Carbamic Acid, [(2E)-3-[4-(1-Methyl-1H-pyrazol-3-yl)phenyl]-2-propenyl]-,(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-Ethyltetradecahydro-3a,7, 9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl Ester; Formula 1′: R₁ is (2E)-3-[4-(1-Methyl-1H-pyrazol-3-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (110 mg, 0.17 mmol), triethylsilane (130 μL, 0.81 mmol), trifluoroacetic acid (70 μL, 0.91 mmol), and the compound from Reference Example 43 (182 mg, 0.86 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 56 mg (39%) of the title compound. MS 838 (M+H)⁺.

EXAMPLE 44 Compound 44 (Formula 1′: R₁ is (2E)-3-[4-(1-Methyl-1H-pyrazol-5-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (110 mg, 0.17 mmol), triethylsilane (130 μL, 0.81 mmol), trifluoroacetic acid (70 μL, 0.91 mmol), and the compound from Reference Example 44 (182 mg, 0.86 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 6 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 82 mg (58%) of the title compound. MS 838 (M+H)⁺.

EXAMPLE 45 Compound 45 (Formula 1′: R₁ is (2E)-3-[4-(5-Nitro-2-pyridinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from Example 1, step G (80 mg, 0.12 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (100 μL, 1.30 mmol), and the compound from Reference Example 45 (158 mg, 0.62 mmol) in CH₃CN (1.5 mL) was heated to 60° C. for 6 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 62 mg (56%) of the title compound. MS 880 (M+H)⁺.

EXAMPLE 46 Compound 46 (Formula 1′: R₁ is (2E)-3-(8-Quinolinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 46 (143 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 32 mg (25%) of the title compound. MS 809 (M+H)⁺.

EXAMPLE 47 Compound 47 (Formula 1′: R₁ is (2E)-3-(7-Quinolinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 47 (143 mg, 0.78 mmol) in CH₃CN (1.0 mL) as heated at 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 40 mg of the title compound mixed with the compound from example 1, step G. This mixture was re-subjected to the above reaction conditions and purified as above to give 15 mg (12%) of the title compound. MS 809 (M+H)⁺.

EXAMPLE 48 Compound 48 (Formula 1′: R₁ is (2E)-3-[6-(1H-Pyrazol-1-yl)-2-pyridinyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 48 (156 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 48 h. An additional amount of the compound from Reference Example (78 mg, 0.39 mmol) was added and heating at 60° C. was continued for an additional 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 24 mg (19%) of the title compound. MS 825 (M+H)⁺.

EXAMPLE 49 Compound 49 (Formula 1′: R₁ is (2E)-3-[6-(1H-Pyrazol-1-yl)-3-pyridinyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (50 mg, 0.078 mmol), triethylsilane (125 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 1.17 mmol), and the compound from Reference Example 22 (78 mg, 0.39 mmol) in CH₃CN (0.5 mL) was heated to 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.4 dichloromethane/methanol/conc. NH₄OH) yielded 44 mg (34%) of the title compound. MS 825 (M+H)⁺.

EXAMPLE 50 Compounds 50 and 51 (Formula 1′, Compounds 50: R₁ is (2E,4E)-5-[6-(1H-1,2,4-Triazol-1-yl)-2-pyridinyl]-2,4-pentadienyl, R₂ is H, R₃ is H, R₄ is H: Compounds 51: R₁ is (2E)-3-[6-(1H-1,2,4-triazol-1-yl)-2-Pyridinyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the mixture of compounds from Reference Example 31 (157 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 48 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 92:8:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 12 mg (9%) of Compound 50 [MS 852 (M+H)⁺] and 16 mg (12%) of Compound 51 [MS 826 (M+H)⁺].

EXAMPLE 51 Compound 52 (Formula 1′: R_(1is ()2E)-3-(4-Isoquinolinyl)-2-propenyl, R₂is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 49 (143 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 72 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 28 mg (22%) of the title compound. MS 809 (M+H)⁺.

EXAMPLE 52 Compound 53 (Formula 1′: R₁ is (2E)-3-[3-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 51 (170 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 102 mg (78%) of the title compound. MS 843 (M+H)⁺.

EXAMPLE 53 Compound 54 (Formula 1′: R₁ is 3,3-Diphenyl-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and β-phenylcinnamaldehyde (163 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 38 mg (29%) of the title compound. MS 834 (M+H)⁺.

EXAMPLE 54 Compound 55 (Formula 1′: R₁ is [3-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 7 (149 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 36 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 93:7:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 78 mg (61%) of the title compound. MS 817 (M+H)⁺.

EXAMPLE 55 Compound 56 (Formula 1′: R₁ is [5-(2-Pyridinyl)-2-thiophenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and 5-(2-pyridinyl)-2-thiophenecarboxaldehyde (148 mg, 0.78 mmol, prepared as described in J. Chem Soc., Perkin Trans. 2 1998, 437) in CH₃CN (1.0 mL) was heated at 60° C. for 72 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 48 mg (38%) of the title compound. MS 815 (M+H)⁺.

EXAMPLE 56 Compound 57 (Formula 1′: R₁ is (2E)-3-[5-(2-Pyridinyl)-2-thienyl]-2-propenyl, R₂ is H, R₃ s H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 52 (170 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 12 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 71 mg (54%) of the title compound. MS 841 (M+H)⁺.

EXAMPLE 57 Compound 58 (Formula 1′: (R₁ is (2E)-3-[3-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 50 (170 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 106 mg (81%) of the title compound. MS 842 (M+H)⁺.

EXAMPLE 58 Compound 59 (Formula 1′: R₁ is [3-Fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 6 (150 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 78 mg (61%) of the title compound. MS 816 (M+H)⁺.

EXAMPLE 59 Compound 60 (Formula 1′: R₁ is (2E,4E)-5-[4-(1H-Pyrazol-1-yl)phenyl]-2,4-pentadienyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (120 mg, 0.19 mmol), triethylsilane (145 μL, 0.91 mmol), trifluoroacetic acid (72 μL, 0.93 mmol), and the compound from Reference Example 53 (210 mg, 0.94 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 98 mg (62%) of the title compound. MS 850 (M+H)⁺.

EXAMPLE 60 Compound 61 (Formula 1′: R₁ is (1-Phenyl-1H-pyrazol-4-yl)methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and 1-phenyl-1H-pyrazol-4-ylcarboxaldehyde (134 mg, 0.78 mmol, prepared as described in Synth. Commun. 1998, 28,1299) in CH₃CN (1.0 mL) was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 86 mg (69%) of the title compound. MS 798 (M+H)⁺.

EXAMPLE 61 Compound 62 (Formula 1′: R₁ is (2E)-3-(1-Phenyl-1H-pyrazol-4-yl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 54 (155 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 46 mg (36%) of the title compound. MS 824 (M+H)⁺.

EXAMPLE 62 Compound 64 (Formula 1′: R₁ is [4-(4-Methyl-1H-pyrazol-1-yl)phenyl]methyl, R₂ is H, R₃ s H, R₄ is H)

A solution of the compound from example 1, step G (110 mg, 0.17 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 4 (152 mg, 0.82 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 70 mg (50%) of the title compound. MS 812 (M+H)⁺.

EXAMPLE 63 Compound 65 (Formula 1′: R₁ is [3-(2-Pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 12 (144 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 72 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 36 mg (29%) of the title compound. MS 810 (M+H)⁺.

EXAMPLE 64 Compound 66 (Formula 1′: R₁ is (2E)-3-[3-(2-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 40 (170 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 3 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 38 mg (27%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 65 Compound 67 (Formula 1′: R₁ is (2E)-3-[4-(4-Methyl-1H-pyrazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 55 (170 mg, 0.80 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 98 mg (69%) of the title compound. MS 838 (M+H)⁺.

EXAMPLE 66 Compound 69 (Formula 1′: R₁ is [4-(4-Methyl-2-pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 14 (156 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 72 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 43 mg (33%) of the title compound. MS 824 (M+H)⁺.

EXAMPLE 67 Compound 68 (Formula 1′: R₁ is (2E)-3-[4-(4-Methyl-2-pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 41 (175 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 78 mg (59%) of the title compound. MS 850 (M+H)⁺.

EXAMPLE 68 Compound 70 (Formula 1′: R₁ is [4-(4-Methoxy-2-pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 13 (167 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 36 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 62 mg (47%) of the title compound. MS 840 (M+H)⁺.

EXAMPLE 69 Compound 71 (Formula 1′: R₁ is (R₁ is (2E)-3-[4-(4-Methoxy-2-pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (150 mg, 0.23 mmol), triethylsilane (180 μL, 1.17 mmol), trifluoroacetic acid (90 μL, 1.17 mmol), and the compound from Reference Example 56 (281 mg, 1.17 mmol) in CH₃CN (2.0 mL) was heated at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 110 mg (55%) of the title compound. MS 866 (M+H)⁺.

EXAMPLE 70 Compound 72 (Formula 1′: R₁ is (2E)-3-(6-Bromo-3-pyridinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 23 (165 mg, 0.79 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.5 dichloromethane/methanol/conc. NH₄OH) yielded 94 mg (72%) of the title compound. MS 837 (M+H)⁺.

EXAMPLE 71 Compound 73 (Formula 1′: R₁ is [2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 8 (148 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.5 dichloromethane/methanol/conc. NH₄OH) yielded 75 mg (59%) of the title compound. MS 816 (M+H)⁺.

EXAMPLE 72 Compound 74 (Formula 1′: R₁ is (2E)-3-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 25 (168 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 58 mg (44%) of the title compound. MS 842 (M+H)⁺.

EXAMPLE 73 Compound 76 (Formula 1′: R₁ is (4-Pyrazinylphenyl)methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 17 (144 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 96 mg (76%) of the title compound. MS 810 (M+H)⁺.

EXAMPLE 74 Compound 77(Carbamic Acid, [(2E)-3-(4-Pyrazinylphenyl)-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-Ethyltetradecahydro-3a,7, 9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl Ester; Formula 1′: R₁ is (2E)-3-(4-Pyrazinylphenyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 57 (164 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 12 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 116 mg (89%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 75 Compound 78 (Formula 1′: R₁ is (2E)-3-[4-(4-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 58 (164 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 121 mg (92%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 76 Compound 79 (Formula 1′: R₁ is [4-(4-Pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 18 (144 mg, 0.78 mmol) in CH₃CN (1.0 ml) is heated at 60° C. for 18 h. Additional triethylsilane (250 μL, 1.56 mmol) and trifluoroacetic acid (120 μL, 1.56 mmol) was added and heating at 60° C. was continued for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 121 mg (92%) of the title compound. MS 810 (M+H)⁺.

EXAMPLE 77 Compound 81 (Formula 1′: R₁ is [3-Methoxy-4-(1H-pyrazol-1-yl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 5 (158 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 82 mg (64%) of the title compound. MS 828 (M+H)⁺.

EXAMPLE 78 Compound 82 (Formula 1′: R₁ is 3-[4-(1H-Pyrazol-1-yl)phenyl]-2-propynyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (50 mg, 0.078 mmol), triethylsilane (75 μL, 0.47 mmol), trifluoroacetic acid (36 μL, 0.47 mmol), and the compound from Reference Example 20 (46 mg, 0.23 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 72 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 22 mg (34%) of the title compound. MS 822 (M+H)⁺.

EXAMPLE 79 Compound 83 (Formula 1′: R₁ is [4-(2-Pyrimidinyloxy)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 9 (156 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 80 mg (62%) of the title compound. MS 826 (M+H)⁺.

EXAMPLE 80 Compound 84 (Formula 1′: R₁ is (2E)-3-[3-Methoxy-4-(1H-pyrazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (250 μL, 1.57 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 26 (178 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated to 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 96:4:0.5 dichloromethane/methanol/conc. NH₄OH) yielded 72 mg (54%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 81 Compound 86 (Formula 1′: R₁ is (2E)-3-[4-(2-Pyrimidinyloxy)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (124 μL, 0.78 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 59 (177 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 50 mg (38%) of the title compound. MS 852 (M+H)⁺.

EXAMPLE 82 Compound 87 (Formula 1′: R₁ is [2-Fluoro-4-(2-pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 15 (158 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 96 mg (74%) of the title compound. MS 828 (M+H)⁺.

EXAMPLE 83 Compound 88 (Formula 1′: R₁ is (2E)-3-[2-Fluoro-4-(2-pyrimidinyl)phenyl]l-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 60 (178 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 106 mg (80%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 84 Compound 92 (Formula 1′: R₁ is (2E)-3-[1-(2-Pyrimidinyl)-1H-imidazol-4-yl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 62 (156 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 36 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 90 mg (70%) of the title compound. MS 826 (M+H)⁺.

EXAMPLE 85 Compound 93 (Formula 1′: R₁ is [1-(2-Pyrimidinyl)-1H-imidazol-4-yl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 10 (136 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 32 mg (26%) of the title compound. MS 800 (M+H)⁺.

EXAMPLE 86 Compound 96 (Formula 1′: R₁ is (2E)-3-[4-(3-Pyridazinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 61 (164 mg, 0.78 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 120 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 50 mg (38%) of the title compound. MS 836 (M+H)⁺.

EXAMPLE 87 Compound 97 (Formula 1′: R₁ is [4-(3-Pyridazinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (100 mg, 0.16 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 16 (144 mg, 0.78 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 28 mg (22%) of the title compound. MS 810 (M+H)⁺.

EXAMPLE 88 Compound 63: 2′-Acetate of the Compound 20

The title compound was prepared from Compound 20 by a procedure analogous to Example 1, step D. MS 867 (M+H)⁺.

EXAMPLE 89 Compound 94: 2′-Acetate of Compound 32 R₁ is (2E)-3-[4-(2-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step F (150 mg, 0.22 mmol), triethylsilane (340 μL, 2.13 mmol), trifluoroacetic acid (170 μL, 2.21 mmol), and the compound from Reference Example 29 (230 mg, 1.09 mmol) in CH₃CN (1.5 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 25-50% acetone/hexane) yielded 80 mg (42%) of the title compound. MS 878 (M+H)⁺.

EXAMPLE 90 Compound 40 (Formula 1′: R₁ is (2E)-3-[4-(4H-1,2,4-Triazol4-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is H)

Step A

A mixture of tin(II) chloride (450 mg, 2.37 mmol) and the compound from Example 17 (Compound 15, 375 mg, 0.47 mmol) in ethanol (10 mL) was heated to reflux for 1 h. The cooled reaction mixture was diluted with 15% aq. NaOH (15 mL) and extracted with dichloromethane (3×15 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 185 mg (5%) of the amine. MS 773 (M+H)⁺.

Step B

N,N-dimethylformamide azine dihydrochloride (32 mg, 0.15 mmol) and the amine from step A (75 mg, 0.097 mol) in pyridine (0.5 mL) were heated to 115° C. for 18 h. The cooled reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.2 dichloromethane/methanol/conc. NH₄OH) followed by a second chromatography (SiO₂, 97:3 acetonitrile/triethylamine) yielded 24 mg (30%) of the title compound. MS 825 (M+H)⁺.

EXAMPLE 91 Compound 17 (Formula 1′: R₁ is [1,1′-Biphenyl]-4-ylmethyl, R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from Example 18 (Compound 16, 50 mg, 0.060 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.0 mg, 0.0035 mmol) in toluene (1.0 mL) was treated with 2 M Na₂CO₃ (1.0 mL) and a solution of phenylboronic acid (8.8 mg, 0.072 mmol) in methanol (1.0 mL). The biphasic mixture was heated to reflux for 4 h. The cooled reaction mixture was diluted with dichloromethane (20 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 97:3:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 36 mg (72%) of the title compound. MS 834 (M+H)⁺.

EXAMPLE 92 Compound 80 (Carbamic Acid, [3-[4-(2-Pyrimidinyl)phenyl]propyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-Ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl Ester; Formula 1′: R₁ is 3-[4-(2-Pyrimidinyl)phenyl]propyl, R₂ is H, R₃ is H, R₄ is H)

10% Pd/C (25 mg) was added to a solution of the compound from Example 33 (Compound 32, 55 mg, 0.066 mmol) and ammonium formate (21 mg, 0.33 mmol) in methanol (1 mL). After 30 min, the catalyst was filtered off through a pad of Celite and the filter cake was washed with methanol (20 mL). The combined filtrate was concentrated and the residue purified by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) to yield 32 mg (58%) of the title compound. MS 838 (M+H)⁺.

EXAMPLE 93 Compound 85 (Formula 1′: R₁ is (2E)-3-[4-(2-Pyrimidinyl)phenyl]-2-propenyl, R₂ is methyl, R₃ is H, R₄ is H)

A solution of the compound from example 33 (Compound 32, 50 mg, 0.060 mmol), triethylsilane 95 μL, 0.59 mmol), trifluoroacetic acid (45 μL, 0.58 mmol), and paraformaldehyde (9 mg, 0.30 mmol) in CH₃CN (1.0 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 33 mg (65%) of the title compound. MS 850 (M+H)⁺.

EXAMPLE 94 Compound 75 (Formula 1″: R₁ is (2E)-3-[4-(2-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is F) Formula 1″

A solution of Compound 105 (92 mg, 0.14 mmol), triethylsilane (225 μL, 1.39 mmol), trifluoroacetic acid (110 μL, 1.43 mmol), and the compound from Reference Example 29 (147 mg, 0.70 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 29 mg (24%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 95 Compound 89 (Formula 1′: R₁ is (2E)-3-[4-(2-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (100 mg, 0.15 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 29 (160 mg, 0.76 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 6 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 71 mg (55%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 96 Compound 90 (Formula 1′: R₁ is (2E)-3-(6-Quinolinyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (100 mg, 0.15 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 28 (140 mg, 0.76 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 6 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 90 mg (72%) of the title compound. MS 827 (M+H)⁺.

EXAMPLE 97 Compound 91 (Formula 1′: R₁ is (2E)-3-[4-(1H-Pyrazol-1-yl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (100 mg, 0.15 mmol), triethylsilane (240 μL, 1.50 mmol), trifluoroacetic acid (120 μL, 1.56 mmol), and the compound from Reference Example 30 (150 mg, 0.76 mmol) in CH₃CN (1.0 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 80 mg (63%) of the title compound. MS 842 (M+H)⁺.

EXAMPLE 98 Compound 98 (Formula 1′: R₁ is (2E)-3-(4-Pyrazinylphenyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is Hydroxy)

Charcoal (500 mg) was added to a solution of the compound from example 74 (Compound 77, 879 mg, 1.05 mmol) in methanol (15 mL) and the mixture was stirred under an air atmosphere for 18 h. The reaction mixture was filtered through a pad of Celite, the filtered solids were rinsed with additional methanol, and the combined filtrate was concentrated. The residue obtained was stirred in a biphasic mixture of dichloromethane (50 mL) and 10% aq. NaHSO₃ (50 mL) for 3 h. The organic layer was separated, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 5-6% methanol in dichloromethane containing 0.2% conc. NH₄OH) yielded 137 mg of recovered starting material and 334 mg (37%) of the title compound. MS 852 (M+H)⁺.

EXAMPLE 99 Compound 99 (Formula 1′: R₁ is (2E)-3-[4-(3-Pyridazinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (66 mg, 0.10 mmol), triethylsilane (80 μL, 0.50 mmol), trifluoroacetic acid (40 μL, 0.52 mmol), and the compound from Reference Example 61 (105 mg, 0.50 mmol) in dichloromethane (0.8 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) followed by a second chromatography (SiO₂, acetone/triethylamine 100:1) yielded 34 mg (40%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 100 Compound 100 (Formula 1′: R₁ is (2E)-3-[4-(4-Pyrimidinyl)phenyl]-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (50 mg, 0.076 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 58 (80 mg, 0.38 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 42 mg (65%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 101 Compound 101 (Formula 1′: R₁ is (2E)-3-(4-Pyrazinylphenyl)-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (50 mg, 0.076 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 57 (80 mg, 0.38 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 26 mg (40%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 102 Compound 102 (Formula 1′: R₁ is [4-(4-Pyrimidinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (60 mg, 0.091 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 18 (84 mg, 0.45 mmol) in dichloromethane (0.6 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 26 mg (35%) of the title compound. MS 828 (M+H)⁺.

EXAMPLE 103 Compound 103 (Formula 1′: R₁ is (2E)-3-[1-(2-Pyrimidinyl)-1H-imidazol-4-yl]-2-propenyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (50 mg, 0.076 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 62 (77 mg, 0.45 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 5 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 24 mg (38%) of the title compound. MS 844 (M+H)⁺.

EXAMPLE 104 Compound 104 (Formula 1′: R₁ is [4-(2-Pyridinyl)phenyl]methyl, R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (50 mg, 0.076 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), the compound from Reference Example 32 (80 mg, 0.38 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (15 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 46 mg (73%) of the title compound. MS 853 (M+H)⁺.

EXAMPLE 105 Alternate Preparation of Compound 100

Step A

The compound of Example 73 (Compound 76) (38 mg, 0.045 mmol) was converted to its 2′-acetate derivative by a procedure analogous to Example 1, step D.

Step B

Sodium hexamethyldisilazide (1.0 M in THF, 68 μL, 0.068 mmol) mmol) was added dropwise to a solution of the product from step A (0.045 mmol) in DMF (1 mL) at −60° C. The mixture was stirred for 20 min at −60° C. and then SELECTFLUOR™ (19 mg, 0.054 mmol) was added. The resulting mixture was stirred for 10 min at −60° C., diluted with ethyl acetate, washed with water and brine, dried (MgSO₄), and concentrated. This material was allowed to stand in methanol for 24 h and then concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 22 mg (56%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 106 Alternate Preparation of Compound 58

Step A

A solution of the compound from example 1, step D (200 mg, 0.23 mmol), triethylsilane (190 μL, 1.19 mmol), trifluoroacetic acid (100 μL, 1.30 mmol), and the compound from Reference Example 50 (244 mg, 1.23 mmol) in CH₃CN (1.5 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 101 mg (50%) of the title compound. MS 886 (M+H)⁺.

Step B

EDCl (104 mg, 0.54 mmol) was added to a solution of the compound from step A (67.5 mg, 0.076 mmol) and dimethyl sulfoxide (0.10 mL, 1.36 mmol) in dichloromethane (1 ml) at 0° C. A solution of pyridinium trifluoroacetate (106 mg, 0.54 mmol) in dichloromethane (1 mL) was added dropwise and the resulting solution was stirred at 0° C. for 2 h before being quenched with water (1 mL). After 5 min, the mixture is diluted with dichloromethane (20 mL), washed with water and brine, dried (MgSO₄), and concentrated. This material was allowed to stand in methanol for 24 h and then concentrated. Purification by chromatography (SiO₂, 94:6:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 53 mg (83%) of the title compound. MS 842 (M+H)⁺.

EXAMPLE 107 Alternate Preparation of the Compound 32

The title compound was prepared by procedures analogous to Example 106 (alternate preparation) by substituting the compound of Reference Example 29 for the compound of Reference Example 50.

EXAMPLE 108 Compound 95

Step A

A solution of the compound from example 1, step E (1.00 g, 1.46 mmol), triethylsilane (1.20 mL, 7.51 mmol), trifluoroacetic acid (0.55 mL, 7.14 mmol), and the compound from Reference Example 29 (1.30 g, 6.18 mmol) in CH₃CN (8 mL) was heated at 60° C. for 29 h. The reaction mixture was diluted with sat. aq. NaHCO₃ (10 mL), extracted with ethyl acetate (2×50 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 3-5% methanol/dichloromethane containing 0.3% conc. NH₄OH) yielded 0.85 g (66%) of the title compound. MS 880 (M+H)⁺.

Step B

The product from step A (23 mg, 0.026 mmol) was allowed to stand in methanol (2 mL) for 21 h and then concentrated. Purification by chromatography (SiO₂, 5-10% methanol/dichloromethane containing 0.3% conc. NH₄OH) yielded 20 mg (91%) of the title compound. MS 838 (M+H)⁺.

EXAMPLE 109 Compound 105 (Formula 1″: R₁ is H, R₂ is H, R₃ is H, R₄ is F)

Sodium hydride (60% in mineral oil, 120 mg, 3.00 mmol) was added to a solution of the compound from Example 1, step f (1.00 g, 1.51 mmol) in DMF (10 mL) at 0° C. After 30 min at 0° C., N-fluorobenzenesulfonimide (570 mg, 1.81 mmol) was added and the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with sat. aq. NaHCO₃ (100 mL), water (2×100 mL) and brine (100 mL), dried (Na₂SO₄), and concentrated. This material was allowed to stand in methanol for 18 h and then concentrated. Purification by chromatography (SiO₂, 96:4:0.2 dichloromethane/methanol/conc. NH₄OH) yielded 182 mg (18%) of the title compound. MS 660 (M+H)⁺.

EXAMPLE 110 Compound 107 (Formula 1′: R₁ is, [2-[[4-(2-Pyrimidinyl)phenyl]methoxy]ethyl], R₂ is H, R₃ is H, R₄ is H)

A solution of the compound from example 1, step G (50 mg, 0.078 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 63 (89 mg, 0.39 mmol) in CH₃CN (0.5 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 22 mg (33%) of the title compound. MS 854 (M+H)⁺.

EXAMPLE 111 Compound 108 (Formula 1′: R₁ is, [2-[[4-(2-Pyrimidinyl)phenyl]methoxy]ethyl], R₂ is H, R₃ is H, R₄ is F)

A solution of the compound from example 2 (50 mg, 0.076 mmol), triethylsilane (120 μL, 0.75 mmol), trifluoroacetic acid (60 μL, 0.78 mmol), and the compound from Reference Example 63 (87 mg, 0.38 mmol) in CH₃CN (0.5 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 95:5:0.1 dichloromethane/methanol/conc. NH₄OH) yielded 50 mg (66%) of the title compound. MS 872 (M+H)⁺.

Reference Example 1 Preparation of 4-Phenylbutanal

4-Phenylbutanol (700 mg, 4.66 mmol) was added to a solution of the Dess-Martin reagent (2.40 g, 5.66 mol) in dichloromethane (35 mL). After 30 min at RT, the solution was quenched with 10% aq. Na₂S₂O₃, washed with sat. aq. NaHCO₃ and brine, dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 9:1 hexane/ethyl acetate) yielded the title compound. MS 149 (M+H)⁺.

Reference Example 2 Preparation of 4-Pyridinepropanal

4-Pyridinepropanol (0.60 mL, 4.65 mmol) was added to a solution of the Dess-Martin reagent (2.37 g, 5.58 mol) in dichloromethane (30 mL). After 60 min at RT, the solution was quenched with 10% aq. Na₂S₂O₃, washed with sat. aq. NaHCO₃ and brine, dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 4:1 hexane/ethyl acetate) yielded the title compound.

MS 136 (M+H)⁺.

Reference Example 3 3-(1H-Pyrazol-1-yl)benzaldehyde

A mixture of 3-formylphenylboronic acid (2.00 g, 13.34 mmol), pyrazole (0.46 g, 6.67 mmol), copper(II) acetate (1.82 g, 10.01 mmol), pyridine (1.10 mL, 13.34 mmol), and powdered 4A molecular sieves (2.5 g) in dichloromethane (20 mL) was stirred under an air atmosphere for 24 h. The mixture was then filtered through Celite, the filtered solids were washed with MeOH, and the combined filtrate was concentrated. Purification by chromatography (SiO₂, 3:1 hexane/ethyl acetate) yielded the title compound.

MS 173 (M+H)⁺.

Reference Example 4 4-(4-Methyl-1H-pyrazol-1-yl)benzaldehyde

A solution of 4-methylpyrazole (1.98 g, 24.11 mmol) in DMF (8 mL) was added to sodium hydride (60% in oil, 0.97 g, 24.25 mmol) in DMF (6 mL) and the resulting mixture was stirred 2 h at RT. 4-Fluorobenzaldehyde (1.26 g, 7.45 mmol) was added dropwise and the resulting mixture heated to 80° C. for 3 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 4:1 hexane/ethyl acetate) followed by recrystallization from hexane yielded the title compound. MS 187 (M+H)⁺.

Reference Example 5 3-Methoxy-4-(1H-pyrazol-1-yl)benzaldehyde

A mixture of 4-fluoro-3-methoxybenzaldehyde (2.00 g, 12.98 mmol), pyrazole (1.32 g, 19.39 mmol), and powdered K₂CO₃ (2.68 g, 19.39 mmol) in DMF (20 mL) was heated to 120° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×200 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 4:1 hexane/ethyl acetate) yielded 1.52 g (58%) of the title compound as a yellow oil. MS 203 (M+H)⁺.

Reference Example 6 3-Fluoro-4-(1H-pyrazol-1-yl)benzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 3,4-difluorobenzaldehyde for the 4-fluoro-3-methoxybenzaldehyde of Reference Example 5. MS 191 (M+H)⁺.

Reference Example 7 3-Fluoro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 3,4-difluorobenzaldehyde and 1,2,4-triazole, respectively, for the 4-fluoro-3-methoxybenzaldehyde and pyrazole of Reference Example 5. MS 192 (M+H)⁺.

Reference Example 8 2-Fluoro-4-(1H-pyrazol-1-yl)benzaldehyde

Step A 2-Fluoro-4-(1H-pyrazol-1-yl)benzonitrile

A mixture of 2-fluoro-4-hydrazinobenzonitrile (3.03 g, 20.05 mmol, prepared as described in U.S. Pat. No. 5,006,148), malonaldehyde bis(diethyl)acetal (4.80 mL, 20.02 mmol), and conc. HCl (1 mL) in ethanol (20 mL) was heated to reflux for 1 h. Upon cooling to RT, the reaction mixture solidified. Water (40 mL) was added and the mixture was cooled to 0° C. and made basic with 10% NaOH. The solids were removed by filtration, washed with water, and dried in vacuo to yield 3.59 g (96%) of the title compound as a light brown solid.

Step B 2-Fluoro-4-(1H-pyrazol-1-yl)benzaldehyde

Diisobutylaluminum hydride (1.0 M in toluene, 11.00 mL, 11.00 mol) was added dropwise over 10 min to a vigorously stirred suspension of the compound from step A (1.88 g, 10.04 mmol) in toluene (100 mL) at −78° C. After 1 h at −78° C., MeOH (1 mL) was added, the mixture was stirred for 5 min, and then poured into a stirred, cold (0° C.) mixture of 1.2 N HCl (100 mL) and ethyl acetate (100 mL). After stirring for 30 min at RT, the layers were separated and the aqueous layer was extracted with additional ethyl acetate (100 mL). The combined organic layers were washed with sat. aq. NaHCO₃ (100 mL) and brine (100 mL), dried (MgSO₄), and concentrated. Recrystallization from IPA followed by chromatography (SiO₂, dichloromethane) provided 1.25 g (65%) of the title compound as a colorless solid. MS 191 (M+H)⁺.

Reference Example 9 4-(2-Pyrimidinyloxy)benzaldehyde

Sodium hydride (60% in oil, 1.44 g, 36.00 mmol) was added to a 0° C. solution of 4-hydroxybenzaldehyde (4.40 g, 36.03 mmol) in DMF (16 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrimidine (4.12 g, 35.97 mmol) in DMF (8 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO₄), and concentrated to provide 6.20 g (86%) of the title compound. MS 201 (M+H)⁺.

Reference Example 10 1-(2-Pyrimidinyl)-1H-imidazole4-carboxaldehyde

The title compound was prepared by a procedure analogous to Reference Example 9 by substituting 1H-imidazole-4-carboxaldehyde for the 4-hydroxybenzaldehyde of Reference Example 9. MS 175 (M+H)⁺.

Reference Example 11 3-(2-Pyridinyl)benzaldehyde

2M aq. Na₂CO₃ (5 mL) and a solution of 3-formylphenylboronic acid (1.14 g, 7.60 mmol) in methanol (5 mL) were added to a solution of 2-bromopyridine (1.00 g, 6.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) in toluene (10 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 4:1 hexane/ethyl acetate) yielded 1.03 g (89%) of the title compound. MS 184 (M+H)⁺.

Reference Example 12 3-(2-Pyrimidinyl)benzaldehyde

A mixture of Na₂CO₃ (4.74 g, 44.72 mmol) and 3-formylphenylboronic acid (3.40 g, 22.67 mmol) in water (15 mL) were added to a solution of 2-bromopyrimidine (3.00 g, 18.87 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.72 g, 0.62 mmol) in DME (30 mL) and the mixture was heated to reflux for 24 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 1:1 hexane/ethyl acetate) yielded 2.20 g (63%) of the title compound. MS 185 (M+H)⁺.

Reference Example 13 4-(4-Methoxy-2-pyrimidinyl)benzaldehyde

1 M aq. Na₂CO₃ (20 mL) and ethanol (10 mL) were added to a solution of 2-chloro-4-methoxypyrimidine (2.90 g, 20.06 mmol, prepared as described in Tetrahedron 1997, 53, 11595), 4-formylphenylboronic acid (3.90 g, 26.01 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.60 g, 0.99 mmol) in toluene (40 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 4:1 hexane/ethyl acetate) yielded 1.80 g (42%) of the title compound. MS 215 (M+H)⁺.

Reference Example 14 4-(4-Methyl-2-pyrimidinyl)benzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 12 by substituting 4-formylphenylboronic acid and 2-bromo-4-methylpyrimidine (prepared as described in Helv. Chim. Acta 1992, 75, 1621) for the 3-formylphenylboronic acid and 2-bromopyridine, respectively, of Reference Example 12. MS 199 (M+H)⁺.

Reference Example 15 2-Fluoro-4-(2-pyrimidinyl)benzaldehyde

Step A

Dimethyl sulfoxide (70 mL) and 4-bromo-2-fluorobenzaldehyde (2.44 g, 12.02 mmol) were added to a mixture of potassium acetate (3.54 g, 36.07 mmol), bis(pinacolato)diboron (3.36 g, 13.23 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (294 mg, 0.36 mmol). The mixture was heated to 80° C. for 18 h. The cooled reaction mixture was diluted with benzene, washed with water, dried (MgSO₄), and concentrated. The material was used in the next step without further purification.

Step B

The title compound was prepared by a procedure analogous to Reference Example 12 by substituting the product of step A for the 3-formylphenylboronic acid of Reference Example 12. MS 203 (M+H)⁺.

Reference Example 16 4-(3-Pyridazinyl)benzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 13 by substituting 3-chloropyridazine (prepared as described in WO 9724124) for the 2-chloro4-methoxypyrimidine of Reference Example 13. MS 185 (M+H)⁺.

Reference Example 17 4-Pyrazinylbenzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 13 by substituting chloropyrazine for the 2-chloro-4-methoxypyrimidine of Reference Example 13. MS 185 (M+H)⁺.

Reference Example 18 4-(4-Pyrimidinyl)benzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 13 by substituting 4-chloropyrimidine hydrochloride (prepared as described in WO 9821188) for the 2-chloro-4-methoxypyrimidine of Reference Example 13. MS 185 (M+H)⁺.

Reference Example 19 4-(5-nitro-2-pyridinyl)benzaldehyde

The title compound was prepared by a procedure analogous to Reference Example 11 by substituting 4-formylphenylboronic acid and 2-bromo-5-nitropyridine for the 3-formylphenylboronic acid and 2-bromopyridine, respectively, of Reference Example 11. MS 229 (M+H)⁺.

Reference Example 20 3-[4-(1H-Pyrazol-1-yl)phenyl]-2-propynal

Step A 3-[4-(1H-Pyrazol-1-yl)phenyl]-2-propyn-1-ol

A mixture of 1-(4-bromophenyl)-1H-pyrazole (prepared as described in Bull. Soc. Chim. Fr. 1966, 2832) (2.24 g, 10.04 mmol), Pd(Ph₃P)₂Cl₂ (180 mg, 0.26 mmol), and copper(I) iodide (95 mg, 0.50 mmol) in TEA (20 mL) was stirred for 5 min, propargyl alcohol (0.70 mL, 12.02 mmol) was added, and the mixture was heated to 80° C. for 48 h. The volatiles were evaporated, ethyl acetate (50 mL) and water (50 mL) were added to the residue, and the mixture was filtered through a pad of Celite. The organic layer from the filtrate was washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 3:2 hexane/ethyl acetate) yielded 0.73 g (37%) of the title compound as a brown solid. MS 199 (M+H)⁺.

Step B 3-[4-(1H-Pyrazol-1-yl)phenyl]-2-propynal

A mixture of the compound from step A (0.71 g, 3.58 mmol) and MnO₂ (3.10 g, 35.66 mmol) in acetone (40 mL) was heated to reflux for 3 h. The cooled reaction mixture was filtered through Celite and the filtrate was concentrated. Purification by chromatography (SiO₂, 6:1 hexane/ethyl acetate) yielded 0.19 g (27%) of the title compound as an off-white solid. MS 197 (M+H)⁺.

Reference Example 21 3-(3-Quinolinyl)-2-propynal

A mixture of 3-(3-quinolinyl)-2-propyn-1-ol (prepared as described in J. Med Chem. 1996, 39, 3179) (360 mg, 1.96 mmol) and the Dess-Martin reagent (1.00 g, 2.36 mmol) in dichloromethane (10 mL) was stirred at RT for 1.5 h. The solution was washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 1:4 hexane/ethyl acetate) yielded 258 mg (72%) of the title compound. MS 182 (M+H)⁺.

Reference Example 22 3-[6-(1H-Pyrazol-1-yl)-3-pyridinyl]-2-propenal

Step A 5-Bromo-2-(1H-pyrazol-1-yl)pyridine

Pyrazole (2.05 g, 30.11 mol) was added in portions to sodium hydride (60% in oil, 1.20 g, 30.00 mmol) in DMF (40 mL) and the resulting mixture was stirred for 1 h at RT. 2,5-Dibromopyridine (4.75 g, 20.05 mmol) was added and the mixture was heated to 100° C. for 2 h. Ice-water (100 mL) was added to the cooled reaction mixture and the precipitated solids were removed by filtration and allowed to air-dry. Recrystallization from hexane provided 3.31 g (74%) of the title compound as a tan solid. MS 224 (M+H)⁺.

Step B Methyl 3-([6-(1H-Pyrazol-1-yl)pyridin-3-yl]-2-propenoate

A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to ⁰° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)⁺.

Step C 3-[6-(1H-Pyrazol-1-yl)-3-pyridinyl]-2-propen-1-ol

DIBAL (1.0 M solution in toluene, 3.10 mL, 3.10 mmol) was added dropwise to a suspension of the compound from step B (350 mg, 1.53 mmol) in toluene (10 mL) and dichloromethane (4 mL) at −78° C. and the mixture was stirred for 2 h at that temperature. MeOH (1 mL) was added and the mixture was poured into a stirring mixture of ethyl acetate (20 mL) and 10% aq. potassium sodium tartrate (20 mL) and stirred for 1 h at RT. The organic layer was washed with brine (20 mL), dried (Na₂SO₄), and concentrated. Purification by chromatography (SiO₂, 1:1 hexane/ethyl acetate) yielded 185 mg (59%) of the title compound. MS 202 (M+H)⁺.

Step D 3-[6-(1H-Pyrazol-1-yl)-3-pyridinyl]-2-propenal

A mixture of the compound from step C (185 mg, 0.92 mmol) and MnO₂ (1.60 g, 18.40 mmol) in acetone (15 mL) was heated to reflux for 1 h. The cooled reaction mixture was filtered through Celite and the filtrate was concentrated. Purification by chromatography (SiO₂, 2:1 hexane/ethyl acetate) yielded 78 mg (43%) of the title compound. MS 200 (M+H)⁺.

Reference Example 23 3-(6-Bromo-3-pyridinyl)-2-propenal

2-Propylmagnesium chloride (2.0 M in THF, 5.00 mL 10.00 mmol) was added to a solution of 2,5-dibromopyridine (2.37 g, 10.00 mmol) in THF (5.0 mL) at RT. The resulting brown suspension was stirred for 1 h and then cooled to 0° C. 3-Dimethylaminoacrolein (95%, 1.30 mL, 12.36 mmol) was added and the mixture was warmed to RT and stirred for 2 h. 2 N HCl was added and after 5 min the mixture was cooled to 0° C. The precipitated solids were removed by filtration and partitioned between ethyl acetate (75 mL) and 10% NaOH (25 mL). The ethyl acetate layer was washed with brine (25 mL), dried (MgSO₄), and concentrated. Recrystallization from ethyl acetate provided 550 mg (26%) of the title compound as shiny brown flakes. MS 211 (M+H)⁺.

Reference Example 24 3-[4-(3-Pyridinyl)phenyl]-2-propenal

2M aq. Na₂CO₃ (1 mL) and a solution of 3-pyridinylboronic acid (148 mg, 1.20 mmol) in methanol (1 mL) were added to a solution of 4-bromocinnamaldehyde (211 mg, 1.00 mmol, prepared as described in Tetrahedron 1998, 54, 10761) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) in toluene (2 mL) and the mixture was heated to reflux for 36 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 1:1 hexane/ethyl acetate) yielded the title compound. MS 210 (M+H)⁺.

Reference Example 25 3-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenal

A mixture of 2-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde (1.06 g, 5.57 mmol, prepared as described in Reference Example 8), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (3.60 g, 8.39 mmol), and TDA-1 (1.80 mL, 5.63 mmol) in dichloromethane (30 mL) and sat. aq. K₂CO₃ (30 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (Na₂SO₄), and concentrated. THF (15 mL) and 10% HCl (15 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and dried in vacuo. Recrystallization from IPA provided 0.84 g (70%) of the title compound as tan needles. MS 217 (M+H)⁺.

Reference Example 26 3-[3-Methoxy-4-(1H-pyrazol-1-yl)phenyl]-2-propenal

A mixture of 3-methoxy-4-(1H-pyrazol-1-yl)benzaldehyde (1.52 g, 7.52 mmol, prepared as described in Reference Example 5), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (4.85 g, 11.30 mmol), and TDA-1 (2.40 mL, 7.50 mmol) in dichloromethane (35 mL) and sat. aq. K₂CO₃ (35 mL) was heated to reflux for 18 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. THF (20 mL) and 10% HCl (20 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 2:1 hexane/ethyl acetate) provided 1.47 g (86%) of the title compound as a yellow solid. MS 229 (M+H)⁺.

Reference Example 27 3-(6-Quinoxalinyl)-2-propenal

A mixture of 6-quinoxalinecarboxaldehyde (0.62 g, 3.92 mmol, prepared as described in Photochem. Photobiol. 1991, 54, 7), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (2.50 g, 5.82 mmol), and TDA-1 (1.20 mL, 3.75 mmol) in dichloromethane (20 mL) and sat. aq. K₂CO₃ (20 mL) was heated to reflux for 4 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated. THF (10 mL) and 10% HCl (10 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and dried in vacuo to give 0.47 g (65%) of the title compound as a tan solid. MS 185 (M+H)⁺.

Reference Example 28 3-(6-Quinolinyl)-2-propenal

A mixture of 6-quinolinecarboxaldehyde (1.58 g, 10.05 mmol, prepared as described in U.S. Pat. No. 5,559,256), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K₂CO₃ (50 mL) was heated to reflux for 5 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. Chromatography (SiO₂, 1:1 hexane/ethyl acetate+0.2% triethylamine) provided a yellow solid that was partioned between ethyl acetate (20 mL) and 10% HCl (15 mL). The aqueous layer was washed with ethyl acetate (2×20 mL) and then made basic with 10% NaOH. The precipitated solids were collected by filtration, washed with water, and dried in vacuo to give 1.20 g (65%) of the title compound as a light yellow solid. MS 184 (M+H)⁺.

Reference Example 29 3-[4-(2-Pyrimidinyl)phenyl]-2-propenal

A mixture of 4-(2-pyrimidinyl)-benzaldehyde (1.83 g, 9.94 mmol, prepared as described in WO 9828264), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K₂CO₃ (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and air-dried. Recrystallization from 2-propanol provided 1.20 g (57%) of the title compound as a light yellow solid. MS 211 (M+H)⁺.

Reference Example 30 3-[4-(1H-Pyrazol-1-yl)phenyl]-2-propenal

A mixture of 4-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) (1.65 g, 9.58 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K₂CO₃ (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 3:1 hexane/ethyl acetate) provided 1.69 g (89%) of the title compound as a yellow solid. MS 199 (M+H)⁺.

Reference Example 31 3-[6-(1H-1,2,4-Triazol-1-yl)-2-pyridinyl]-2-propenal and 5-[6-(1H-1,2,4-triazol-1-yl)-2-pyridinyl]-2,4-pentadienal

Step A

A solution of 1,2,4-triazole (1.55 g, 22.35 mmol) in DMF (7 mL) was added to sodium hydride (60% in oil, 0.90 g, 22.50 mmol) in DMF (7 mL) and the resulting mixture was stirred 2 h at RT. 2-(1,3-Dioxolan-2-yl)-6-fluoropyridine (1.26 g, 7.45 mmol, prepared as described in J. Med. Chem. 1998, 41, 5070) was added dropwise and the resulting mixture heated to 80° C. for 3 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO₄), and concentrated. The residue obtained was dissolved in a mixture of formic acid (12 mL) and water (3 mL), CuSO₄5H₂O (0.19 g, 0.76 mmol) was added, and the mixture was heated to 65° C. for 5 h. The reaction mixture was concentrated, diluted with 10% aq. NaOH to pH>10, and extracted with ethyl acetate. The combined organic extracts were washed with dilute aq. ammonium hydroxide and brine, dried (MgSO₄), and concentrated. The material was used in the next step without further purification.

Step B

A mixture of the product from step A (0.80 g, 4.59 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (3.00 g, 6.99 mmol), and TDA-1 (2.00 mL, 6.25 mmol) in dichloromethane (20 mL) and sat. aq. K₂CO₃ (20 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated. THF (10 mL) and 10% HCl (10 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 2:1 hexane/ethyl acetate) provided 0.40 g (43%) of an inseparable mixture of 3-[6-(1H-1,2,4-triazol-1-yl)-2-pyridinyl]-2-propenal [MS 201 (M+H)⁺] and 5-[6-(1H-1,2,4-triazol-1-yl)-2-pyridinyl]-2,4-pentadienal [MS 227 (M+H)⁺].

Reference Example 32 3-[4-(2-Pyridinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-benzaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)⁺.

Reference Example 33 3-[4-(4-Pyridinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyridinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)⁺.

Reference Example 34 3-[4-(5-Pyrimidinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-pyrimidinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)⁺.

Reference Example 35 3-[4-(1H-1,2,4-Triazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,4-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)⁺.

Reference Example 36 3-[4-(1H-1,2,3-Triazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,3-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)⁺.

Reference Example 37 3-[4-(1H-Imidazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-imidazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)⁺.

Reference Example 38 3-(4-Quinolinyl)-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-quinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)⁺.

Reference Example 39 3-[3-(2-Pyridinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 11) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)⁺.

Reference Example 40 3-[3-(2-Pyrimidinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 12) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)⁺.

Reference Example 41 3-[4-(4-Methyl-2-pyrimidinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 14) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)⁺.

Reference Example 42 3-[3-(1H-Pyrazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 3) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)⁺.

Reference Example 43 3-[4-(1-Methyl-1H-pyrazol-3-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)⁺.

Reference Example 44 3-[4-(1-Methyl-1H-pyrazol-5-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-5-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)⁺.

Reference Example 45 3-[4-(5-Nitro-2-pyridinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-nitro-2-pyridinyl)benzaldehyde (prepared as described in Reference Example 19) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 255 (M+H)⁺.

Reference Example 46 3-(8-Quinolinyl)-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 8-quinolinecarboxaldehyde (prepared as described in J. Am. Chem. Soc. 1997, 119, 8891) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)⁺.

Reference Example 47 3-(7-Quinolinyl)-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)⁺.

Reference Example 48 3-[6-(1H-Pyrazol-1-yl)-2-pyridinyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30.

MS 200 (M+H)⁺.

Reference Example 49 3-(4-Isoquinolinyl)-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-isoquinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)⁺.

Reference Example 50 3-[3-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde (prepared as described in Reference Example 6) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)⁺.

Reference Example 51 3-[3-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(l H-1,2,4-triazol-1-yl)benzaldehyde (prepared as described in Reference Example 7) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 218 (M+H)⁺.

Reference Example 52 3-[5-(2-Pyridinyl )-2-thienyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyridinyl)-2-thiophenecarboxaldehyde (prepared as described in J. Chem Soc., Perkin Trans. 2 1998, 437) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)⁺.

Reference Example 53 5-[4-(1H-Pyrazol-1-yl)phenyl]-2,4-pentadienal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-[4-(1H-pyrazol-1-yl)phenyl]-2-propenal (prepared as described in Reference Example 30) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)⁺.

Reference Example 54 3-(1-Phenyl-1H-pyrazol-4-yl)-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-phenyl-1H-pyrazol-4-ylcarboxaldehyde (prepared as described in Synth. Commun. 1998, 28, 1299) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)⁺.

Reference Example 55 3-[4-(4-Methyl-1H-pyrazol-1-yl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 4) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)⁺.

Reference Example 56 3-[4-(4-Methoxy-2-pyrimidinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methoxy-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 13) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 241 (M+H)⁺.

Reference Example 57 3-(4-Pyrazinylphenyl)-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-pyrazinylbenzaldehyde (prepared as described in Reference Example 17) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)⁺.

Reference Example 58 3-[4-(4-Pyrimidinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 18) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)⁺.

Reference Example 59 3-[4-(2-Pyrimidinyloxy)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyloxy)benzaldehyde (prepared as described in Reference Example 9) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 227 (M+H)⁺.

Reference Example 60 3-[2-Fluoro-4-(2-pyrimidinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 2-fluoro-4-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 15) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 229 (M+H)⁺.

Reference Example 61 3-[4-(3-Pyridazinyl)phenyl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(3-pyridazinyl)benzaldehyde (prepared as described in Reference Example 16) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)⁺.

Reference Example 62 3-[1-(2-Pyrimidinyl)-1H-imidazol-4-yl]-2-propenal

The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-(2-pyrimidinyl)-1H-imidazole-4-carboxaldehyde (prepared as described in Reference Example 10) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)⁺.

Reference Example 63 [[4-(2-pyrimidinyl)phenyl]methoxy]acetaldehyde

Step A 4-(2-Pyrimidinyl)benzenemethanol

The title compound was prepared by a procedure analogous to Reference Example 12 by substituting 4-(hydroxymethyl)phenylboronic acid for the 3-formylphenylboronic acid of Reference Example 12. MS 187 (M+H)⁺.

Step B [[4-(2-Pyrimidinyl)phenyl]methoxy]acetaldehyde

A solution of the product from step A (559 mg, 3.00 mmol) in DMF (4 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 144 mg, 3.60 mmol) at 0° C. The solution was stirred for 30 min at 0° C., bromoacetaldehyde diethyl acetal (0.55 mL, 3.66 mmol) and tetrabutylammonium iodide (111 mg, 0.30 mmol) were added, and the resulting mixture was stirred at 70° C. for 12 h. Additional sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) and bromoacetaldehyde diethyl acetal (0.55 mL, 3.66 mmol) were added and heating at 70° C. was continued for 12 h. The reaction mixture was concentrated, the residue was diluted with water and extracted with ethyl acetate, the combined organic layers were dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 1:1 hexane/ethyl acetate) gave material which was taken up in ethanol (2 mL) and 10% aq. HCl (10 mL) and stirred for 12 h. The reaction mixture was made basic with aq. NaOH, extracted with ethyl acetate, dried (MgSO₄), and concentrated. Purification by chromatography (SiO₂, 1:1 hexane/ethyl acetate) provided 80 mg (12%) of the title compound. MS 229 (M+H)⁺.

The invention has been described in detail with particular reference to the above embodiments thereof. The above embodiments and examples are given to illustrate the scope and spirit of the present invention. These embodiments and examples will make apparent, to those skilled in the art, other embodiments and examples. These other embodiments and examples are within the contemplation of the present invention. It will be understood that variations and modifications can be effected within the spirit and scope of the invention; therefore, the instant invention should be limited only by the appended claims. 

We claim:
 1. A compound of Formula 1

wherein R¹ and R² are independently selected from the group consisting of hydrogen, optionally substituted C₁-C₈-alkyl, optionally substituted —CH₂C₂-C₈-alkenyl, and optionally substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R¹ and R² are not both hydrogen; R³ is hydrogen; R⁴ is selected from the group consisting of hydrogen, halogen, and hydroxy; R⁵ is hydrogen or a hydroxy protecting group; R⁶ is selected from the group consisting of hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group; X and X′, together with the carbon atom to which they are attached, form C═O, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; and Y and Y′, together with the carbon atom to which they are attached, form C═O, —CHOH, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
 2. The compound of claim 1 wherein: R¹ and R² are independently selected from the group consisting of hydrogen, substituted C₁-C₈-alkyl, substituted —CH₂C₂-C₈-alkenyl, and substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from the group consisting of CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R¹ and R² are not both hydrogen; R³ is hydrogen; R⁴ is selected from the group consisting of hydrogen, halogen, and hydroxy; R⁵ is hydrogen or a hydroxy protecting group; R⁶ is selected from the group consisting of hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group; X and X′, together with the carbon atom to which they are attached, form C═O, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; and Y and Y′, together with the carbon atom to which they are attached, form C═O, —CHOH, C═NR_(c), or C═NOR_(c), wherein R_(c) is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
 3. The compound of claim 2 wherein R¹ and R² are selected from the group consisting of hydrogen, C₁-C₈-alkyl, —CH₂C₂-C₈-alkenyl, and —CH₂C₂-C₈-alkynyl, said C₁-C₈-alkyl, —CH₂C₂-C₈-alkenyl, and —CH₂C₂-C₈-alkynyl being substituted with one or more members selected from the group consisting of —OR_(a) wherein R_(a) is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl, provided that R¹ and R² are not both hydrogen.
 4. The compound of claim 2 wherein R⁴ is hydrogen, X and X′ form C═O together with the carbon atom to which they are attached, and Y and Y′ form C═O together with the carbon atom to which they are attached.
 5. The compound of claim 1 wherein R⁴ is fluorine.
 6. The compound of claim 1 wherein R⁴ is fluorine, X and X′ form C═O together with the carbon atom to which they are attached, and Y and Y′ form C═O together with the carbon atom to which they are attached.
 7. The compound of claim 5 wherein: R¹ and R² are independently selected from the group consisting of hydrogen, substituted C₁-C₈-alkyl, substituted —CH₂C₂-C₈-alkenyl, and substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from the group consisting of CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R¹ and R² are not both hydrogen; R³ is hydrogen; R⁵ is hydrogen or a hydroxy protecting group; R⁶ is selected from the group consisting of hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group.
 8. The compound of claim 7 wherein X and X′ form C═O together with the carbon atom to which they are attached, and Y and Y′ form C═O together with the carbon atom to which they are attached.
 9. The compound of claim 1 wherein R⁶ is ethyl.
 10. The compound of claim 2 wherein R⁶ is ethyl.
 11. The compound of claim 3 wherein R⁶ is ethyl.
 12. The compound of claim 4 wherein R⁶ is ethyl.
 13. The compound of claim 5 wherein R⁶ is ethyl.
 14. The compound of claim 6 wherein R⁶ is ethyl.
 15. The compound of claim 7 wherein R⁶ is ethyl.
 16. The compound of claim 8 wherein R⁶ is ethyl.
 17. Compound of formula 1′ or 1″:

wherein R¹ and R² are independently selected from the group consisting of hydrogen, substituted C₁-C₈-alkyl, substituted —CH₂C₂-C₈-alkenyl, and substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from the group consisting of CN, nitro, -COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R¹ and R² are not both hydrogen; R³ is hydrogen; R⁴ is selected from the group consisting of hydrogen, halogen, and hydroxy; or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, ester or pro-drugs thereof.
 18. The compound of claim 17 wherein R¹ and R² are selected from the group consisting of C₁-C₈-alkyl, —CH₂C₂-C₈-alkenyl, and —CH₂C₂-C₈-alkynyl, said C₁-C₈-alkyl, —CH₂C₂-C₈-alkenyl, and —CH₂C₂-C₈-alkynyl being optionally substituted with one or more members selected from the group consisting of —OR_(a) wherein R_(a) is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl.
 19. The compound of claim 17 wherein R⁴ is flouro.
 20. The compound of claim 18 wherein R⁴ is fluoro.
 21. The compound of claim 1 wherein R⁵ is selected from the group consisting of acyl and aroyl.
 22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is carbamic acid, [(2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester.
 23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is carbamic acid, [(2E)-3-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7, 9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester.
 24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is carbamic acid, [(2E)-3-(4-pyrazinylphenyl)-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R, 15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester.
 25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is carbamic acid, [3-[4-(2-pyrimidinyl)phenyl]propyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7, 9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester.
 26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 27. A method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula I as defined in claim
 1. 28. A method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1 as defined in claim
 1. 29. The method of claim 27 or 28 wherein said condition is selected from community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.
 30. The method of claim 27 or 28 wherein said bacterium is selected from S. aureus, S. epidermidis, S. pneumoniae, Enterococcus spp., Moraxella catarrhalis and H. influenzae.
 31. The method of claim 27 or 28 wherein said bacterium is a Gram-positive coccus.
 32. The method of claim 27 wherein said Gram-positive coccus is antibiotic-resistant.
 33. The method of claim 32 wherein said Gram-positive coccus is erythromycin-resistant.
 34. A process for the preparation of a compound having the formula:

wherein R⁵ is hydrogen or a hydroxy protecting group; R⁷ is a hydroxy protecting group; and R⁶ is selected from the group consisting of hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group; the process comprising: a) treating a compound having the formula

 wherein R⁸ is a hydroxy protecting group and R⁶ and R⁷ are as previously defined, with trichloroacetylisocyanate in an inert solvent to give a compound having the formula

 wherein R⁶, R⁷, and R⁸ are as previously defined; b) treating the compound obtained in step (a) with a suitable base in an aqueous solvent mixture to give a compound having the formula

 wherein R⁵, R⁶, and R⁷ are as previously defined; c) optionally treating the compound obtained in step (b) with an equilibrating base; and d) when R⁵ is hydrogen, optionally protecting the 2′-hydroxy with a hydroxy protecting group.
 35. A process for the preparation of a compound having the formula:

wherein R¹ is selected from the group consisting of hydrogen, optionally substituted C₁-C₈-alkyl, optionally substituted —CH₂C₂-C₈alkenyl, and optionally substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; R⁵ is hydrogen or a hydroxy protecting group; R₆ is selected from the group consisting of hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group; the process comprising: a) treating a compound having the formula

 wherein R⁷ is a hydroxy protecting group, and R⁵ and R⁶ are as previously defined, with a suitably substituted aldehyde, an acid, and a silane reducing agent; b) when R⁵ is hydrogen, protecting the 2′-hydroxy with a hydroxy protecting group; c) oxidizing the 3-hydroxy group; and d) optionally deprotecting the 2′-hydroxy group.
 36. A process for the preparation of a compound having the formula:

wherein R¹ is selected from the group consisting of hydrogen, optionally substituted C₁-C₈-alkyl, optionally substituted —CH₂C₂-C₈-alkenyl, and optionally substituted —CH₂C₂-C₈-alkynyl, wherein the substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR_(a), —OCOR_(a), —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —CONR_(a)R_(b), —OCONR_(a)R_(b), —NHCOR_(a), —NHCOOR_(a), and —NHCONR_(a)R_(b), wherein R_(a) and R_(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; R⁵ is hydrogen or a hydroxy protecting group; R⁶ is selected from the group consisting of hydrogen, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C₁-C₁₀)alkyl, aryl(C₂-C₁₀)alkenyl, aryl(C₂-C₁₀)alkynyl, heterocyclo(C₁-C₁₀)alkyl, heterocyclo(C₂-C₁₀)alkenyl, and heterocyclo(C₂-C₁₀)alkynyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group; the process comprising: a) treating a compound having the formula

 wherein R⁸ is a hydroxy protecting group, and R¹ and R⁶ are as previously defined, with a fluorinating agent in the presence of a base; and b) optionally deprotecting the 2′-hydroxy group.
 37. The process of claim 36 wherein the fluorinating agent is from 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) and sodium hexamethyldisilazide in DMF, N-fluorobenzenesulfonimide and potassium t-butoxide in THF, or N-fluorobenzenesulfonimide and sodium hydride in DMF. 